Alzheimer’s disease (AD), a primary cause of dementia globally, is traditionally diagnosed via cerebrospinal fluid (CSF) measures and positron emission tomography (PET). The invasiveness, cost, and limited accessibility of these methods have led to exploring blood-based biomarkers as a promising alternative for AD diagnosis and monitoring. Recent advancements in sensitive immunoassays have identified potential blood-based biomarkers, such as Aβ42/Aβ40 ratios and phosphorylated tau (p-tau) species. This paper briefly evaluates the clinical utility and reliability of these biomarkers across various AD stages, highlighting challenges like refining plasma Aβ42/Aβ40 assays and enhancing the precision of p-tau, particularly p-tau181, p-tau217, and p-tau231. The discussion also covers other plasma biomarkers like neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and synaptic biomarkers, assessing their significance in AD diagnostics. The need for ongoing research and development of robust assays to match the performance of CSF and PET biomarkers is underscored. In summary, blood-based biomarkers are increasingly crucial in AD diagnosis, follow-up, prognostication, treatment response evaluation, and population screening, particularly in primary care settings. These developments are set to revolutionize AD diagnostics, offering earlier and more accessible detection and management options.

Neurobiomarkers have attracted significant attention over the last ten years. One promising biomarker is the neurofilament light chain protein (NfL). Since the introduction of ultrasensitive assays, NfL has been developed into a widely used axonal damage marker of relevance to the diagnosis, prognostication, follow-up, and treatment monitoring of a range of neurological disorders, including multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer’s disease. The marker is increasingly used clinically, as well as in clinical trials. Even if we have validated precise, sensitive, and specific assays for NfL quantification in both cerebrospinal fluid and blood, there are analytical, as well as pre- and post-analytical aspects of the total NfL testing process, including biomarker interpretation, to consider. Although the biomarker is already in use in specialised clinical laboratory settings, a more general use requires some further work. In this review, we provide brief basic information and opinions on NfL as a biomarker of axonal injury in neurological diseases and pinpoint additional work needed to facilitate biomarker implementation in clinical practice.

Background: Impaired kidney function has a potential confounding effect on blood biomarker levels, including biomarkers for Alzheimer’s disease (AD). Given the imminent use of certain blood biomarkers in the routine diagnostic work-up of patients with suspected AD, knowledge on the potential impact of comorbidities on the utility of blood biomarkers is important. We aimed to evaluate the association between kidney function, assessed through estimated glomerular filtration rate (eGFR) calculated from plasma creatinine and AD blood biomarkers, as well as their influence over predicting Aβ-positivity. Methods: We included 242 participants from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort, comprising cognitively unimpaired individuals (CU; n = 124), mild cognitive impairment (MCI; n = 58), AD dementia (n = 34), and non-AD dementia (n = 26) patients all characterized by [¹⁸F] AZD-4694. Plasma samples were analyzed for Aβ42, Aβ40, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), tau phosphorylated at threonine 181 (p-tau181), 217 (p-tau217), 231 (p-tau231) and N-terminal containing tau fragments (NTA-tau) using Simoa technology. Kidney function was assessed by eGFR in mL/min/1.73 m², based on plasma creatinine levels, age, and sex. Participants were also stratified according to their eGFR-indexed stages of chronic kidney disease (CKD). We evaluated the association between eGFR and blood biomarker levels with linear models and assessed whether eGFR provided added predictive value to determine Aβ-positivity with logistic regression models. Results: Biomarker concentrations were highest in individuals with CKD stage 3, followed by stages 2 and 1, but differences were only significant for NfL, Aβ42, and Aβ40 (not Aβ42/Aβ40). All investigated biomarkers showed significant associations with eGFR except plasma NTA-tau, with stronger relationships observed for Aβ40 and NfL. However, after adjusting for either age, sex or Aβ-PET SUVr, the association with eGFR was no longer significant for all biomarkers except Aβ40, Aβ42, NfL, and GFAP. When evaluating whether accounting for kidney function could lead to improved prediction of Aβ-positivity, we observed no improvements in model fit (Akaike Information Criterion, AIC) or in discriminative performance (AUC) by adding eGFR to a base model including each plasma biomarker, age, and sex. While covariates like age and sex improved model fit, eGFR contributed minimally, and there were no significant differences in clinical discrimination based on AUC values. Conclusions: We found that kidney function seems to be associated with AD blood biomarker concentrations. However, these associations did not remain significant after adjusting for age and sex, except for Aβ40, Aβ42, NfL, and GFAP. While covariates such as age and sex improved prediction of Aβ-positivity, including eGFR in the models did not lead to improved prediction for any biomarker. Our findings indicate that renal function, within the normal to mild impairment range, does not seem to have a clinically relevant impact when using highly accurate blood biomarkers, such as p-tau217, in a biomarker-supported diagnosis.

Objectives: This study aimed to compare serum levels of brain‐derived neurotrophic factor (BDNF) and neurofilament light (NfL) chain in normal individuals and patients with mild and moderate‐severe obstructive sleep apnea syndrome (OSAS).Methods: We enrolled 81 subjects referred to Otorhinolaryngology (Ear‐Nose‐Throat), Gazi University Faculty of Medicine, between 2017 and 2019. Based on the severity of OSAS, patients were divided into three groups: group 1 with mild OSAS (apnea‐hypopnea index [AHI] 5‐15; n = 26), group 2 with moderate‐severe OSAS (AHI > 15; n = 32), and group 3 with normal individuals (AHI scores < 5; n = 23).Results: Serum NfL and BDNF levels were evaluated together with the clinical data for all subjects. Significant differences were seen in the oxygen desaturation index (ODI), apnea index, hypopnea index, sleep efficiency, and NfL levels (P < .05) between the three groups. In the moderate‐severe group, NfL levels showed a significant positive correlation with apnea index (P < .05,r = .389), hypopnea index (P < .05,r = .455), and ODI (P = .04;r = .362).Conclusions: Our findings clarify the pathophysiology of OSAS in cases of repetitive hypoxia and chronic neuronal damage. Based on our results, we recommend that in addition to BDNF, NfL should also be evaluated in different and larger patient cohorts.

BACKGROUND 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). METHODS 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. FINDINGS 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. INTERPRETATION 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. FUNDING Alzheimer’s Association (#ADSF-24-1284328-C) Evidence before this study Phosphorylated tau (p-tau) in cerebrospinal fluid is an established biomarker of Alzheimer’s disease (AD), and several studies of plasma phosphorylated tau (p-tau) biomarkers now show evidence for its diagnostic accuracy in AD. We reviewed the literature on plasma p-tau in AD by searching without language restrictions in PubMed for articles from 1^st January 2014 to 1^st March 2024 using the terms ((("Alzheimer Disease"[Mesh]) OR ((Alzheimer[Title/Abstract]) OR (Alzheimer’s [Title/Abstract))) AND ((("Blood"[Mesh]) OR ("Plasma"[Mesh])) OR (plasma[Title/Abstract]))) AND ((phospho tau[Title/Abstract]) OR (phosphorylated tau[Title/Abstract]) OR (p-tau[Title/Abstract]) OR (P-tau[Title/Abstract]) OR (pTau[Title/Abstract])), filtering for studies in humans. Several studies examined plasma p-tau181, p-tau217 and p-tau231 in well-characterised research cohorts including cognitively impaired and unimpaired individuals, demonstrating high diagnostic accuracy when utilising CSF or amyloid PET imaging “gold standard” biomarkers, and in relation to post-mortem amyloid and tau pathology. Most studies utilised single-method assays to measure biomarkers of interest, including immunoprecipitation-mass spectrometry and a variety of immunochemical methods including single molecule array, enzyme-linked immunosorbent assays, electrochemiluminescence, and immunomagnetic reduction. Some later studies have performed cross-method and cross-phospho-form comparisons (p-tau181, p-tau217 and p-tau231), including six single molecular array assays in the Amsterdam Dementia Cohort, nine assays in the BIODEGMAR memory clinic-based cohort from Spain, ten assays in individuals with mild cognitive impairment in the Skåne University memory clinic cohort from Sweden, and have generally reported the various individual methods for p-tau217 to have the highest diagnostic accuracy for the presence of cerebral β-amyloid deposition. No study to date has compared assays for p-tau217 on semi- and fully automated platforms, described comparisons with p-tau212 and p-tau205 in plasma, or assessed commutability of candidate reference materials between assays in comparison to patient samples. Added value of this study Our study included the largest number of methods for assaying plasma p-tau to date, with engagement from 12 assay developers, allowing for blinded cross-assay comparisons of 33 plasma assays (for p-tau181, p-tau205, p-tau212, p-tau217, and p-tau231). Among these were included several semi-automated and fully automated methods that have potential for widespread clinical application. This is also the first study, to our knowledge, in which the commutability of candidate reference materials was assessed for plasma p-tau, as a first step in efforts to standardise between assays. The study design capitalised on a large volume of paired CSF and plasma drawn from well-characterised attenders to a specialist cognitive disorders service, allowing for 26 intra-method comparisons between CSF and plasma measurements within the same individuals. We found that CSF p-tau217 assays consistently outperformed other CSF p-tau assays in terms of fold-change between individuals with and without Alzheimer’s pathology, and the top ten assays in terms of fold change in plasma were also p-tau217 assays. This high discriminative value of plasma p-tau217 contrasted with overall only moderate correlations between CSF and plasma within individuals, which did not persist within the AD group alone. We also did not observe commutability of the four types of candidate reference materials we investigated, for any of the assay pairs. Implications of all the available evidence Our study adds to the growing evidence for plasma p-tau217 as a candidate biomarker for translation into clinical practice by virtue of its superior discriminative ability between AD vs non-AD in symptomatic individuals, when compared head-to-head with other phosphorylated tau forms. The observed high and clinically interpretable fold-changes are pivotal for this biomarker’s possible future success. Further studies should examine whether blood biomarker-supported diagnosis will extend access to disease-specific (and potentially disease-modifying) treatments and impact patient-relevant outcomes such as quality of life, particularly in diverse and resource-limited settings. Standardization between different assays will also be important for real-world applications, and this will require further concerted efforts in developing reference materials.

Standard surgical procedures for hydrocele may cause postoperative discomfort, temporary limitation of normal activities and complications, such as hematoma, infection, persistent swelling, chronic pain and decreased fertility. We describe a new technique in an effort to decrease these complications. Between April 2004 and December 2006, 21 patients underwent hydrocelectomy, which was bilateral in 1. Through a 15 mm transverse scrotal incision the tunica vaginalis parietalis was identified and grasped. Under gentle traction the sac was dissected bluntly and delivered out of the incision. The fully mobilized tunica was excised by electrocautery at its base, followed by wound closure. Patients were discharged home within 24 hours after surgery and were followed at 6-month intervals for a minimum of 18 months. Mean operative time was 27.3 minutes. Postoperatively hematoma or wound infection was not evident in any case. Mild scrotal edema usually subsided within a few days after the procedure. Two patients with persistent edema and hardening of the scrotum required additional bed rest and anti-inflammatory agents. Patients were able to resume normal daily activity an average of 6 days after surgery (range 3 to 21). Cure was achieved in 21 of the 22 hydrocele cases (95%). Our pull-through technique enables the surgeon to remove large hydrocele sacs through a small incision and with minimal dissection under direct vision of the testicular structures, resulting in early recovery and minimal complications. This procedure may be a viable option for the surgical management of idiopathic hydrocele.