Background The cerebrospinal fluid (CSF) biomarkers amyloid beta 1–42, total tau, and phosphorylated tau are used increasingly for Alzheimer’s disease (AD) research and patient management. However, there are large variations in biomarker measurements among and within laboratories. Methods Data from the first nine rounds of the Alzheimer’s Association quality control program was used to define the extent and sources of analytical variability. In each round, three CSF samples prepared at the Clinical Neurochemistry Laboratory (Mölndal, Sweden) were analyzed by single-analyte enzyme-linked immunosorbent assay (ELISA), a multiplexing xMAP assay, or an immunoassay with electrochemoluminescence detection. Results A total of 84 laboratories participated. Coefficients of variation (CVs) between laboratories were around 20% to 30%; within-run CVs, less than 5% to 10%; and longitudinal within-laboratory CVs, 5% to 19%. Interestingly, longitudinal within-laboratory CV differed between biomarkers at individual laboratories, suggesting that a component of it was assay dependent. Variability between kit lots and between laboratories both had a major influence on amyloid beta 1–42 measurements, but for total tau and phosphorylated tau, between-kit lot effects were much less than between-laboratory effects. Despite the measurement variability, the between-laboratory consistency in classification of samples (using prehoc-derived cutoffs for AD) was high (>90% in 15 of 18 samples for ELISA and in 12 of 18 samples for xMAP). Conclusions The overall variability remains too high to allow assignment of universal biomarker cutoff values for a specific intended use. Each laboratory must ensure longitudinal stability in its measurements and use internally qualified cutoff levels. Further standardization of laboratory procedures and improvement of kit performance will likely increase the usefulness of CSF AD biomarkers for researchers and clinicians.

Wilson's disease (WD) is a genetic disorder affecting Cu metabolism, which can lead to severe physiological and neurological symptoms, and even death if untreated. Based on the fact that WD patients show low Cu levels in serum, implementation of screening programs for diagnosis of this condition at the moment of birth, when progression of the disease can be still arrested, has been attempted in the past. These attempts, however, have been unsuccessful, as healthy new-borns often show low Cu levels in serum due to liver immaturity. In this work, the potential use of isotopic analysis of Cu in serum samples as an alternative diagnostic parameter for Wilson's disease has been investigated. For this purpose, the Cu isotopic composition of a set of serum samples from different groups showing either low (i.e. WD patients, patients who had undergone bariatric surgery, infants) or normal (supposedly healthy adults) Cu concentration levels was determined by means of multi-collector ICP-mass spectrometry (MC-ICP-MS), after chromatographic isolation of Cu. For this purpose, AG-MP-1 strong anion exchange resin was relied upon, enabling quantitative recovery of Cu in pure form from the serum samples. MC-ICP-MS measuring conditions were optimized to avoid the influence of spectral overlap, and Ni was admixed as an internal standard for correction of instrumental mass discrimination. The use of this optimized method provided delta Cu-65 for the serum samples with a typical analytical uncertainty of similar to 0.20 parts per thousand (k = 2). Our results show that, for the population considered in this study, combination of Cu concentration values and Cu isotopic information allows classification of WD patients, infants and controls into different groups, while the use of concentration values only is not sufficient for this purpose. Although further studies with a larger number of samples are needed, results are encouraging as far as the use of Cu isotopic analysis for early diagnosis of Wilson's disease is concerned

This article examines the increasing importance of dried matrix spot (DMS) specimens (such as dried blood spots, dried urine spots, etc.) in biomedical research, the challenges associated with their analysis when quantitative elemental information is aimed at, as well as the benefits deriving from the further usage of these types of samples. The article briefly reviews the historical evolution of this sampling approach in elemental clinical analysis, stressing prospective areas of applications (e.g., newborns or prosthesis control), the methodologies most recently developed to produce DMS of known volume, as well as novel strategies proposed to analyze them, often related to direct solid sampling techniques or fast lixiviation methods. Finally, the article discusses the type of information that could be obtained after isotopic analysis of DMS when targeting non-traditional stable isotopes (e.g., Cu, Fe or Zn), which can significantly help in the early diagnosis of some medical conditions (e.g. Wilson's disease).

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Collection of biological fluids on clinical filter papers shows important advantages from a logistic point of view, although analysis of these specimens is far from straightforward. Concerning urine analysis, and particularly when direct trace elemental analysis by laser ablation-inductively coupled plasma mass spectrometry (LA-ICPMS) is aimed at, several problems arise, such as lack of sensitivity or different distribution of the analytes on the filter paper, rendering obtaining reliable quantitative results quite difficult. In this paper, a novel approach for urine collection is proposed, which circumvents many of these problems. This methodology consists on the use of precut filter paper discs where large amounts of sample can be retained upon a single deposition. This provides higher amounts of the target analytes and, thus, sufficient sensitivity, and allows addition of an adequate internal standard at the clinical lab prior to analysis, therefore making it suitable for a strategy based on unsupervised sample collection and ulterior analysis at referral centers. On the basis of this sampling methodology, an analytical method was developed for the direct determination of several elements in urine (Be, Bi, Cd, Co, Cu, Ni, Sb, Sn, Tl, Pb, and V) at the low μg L(-1) level by means of LA-ICPMS. The method developed provides good results in terms of accuracy and LODs (≤1 μg L(-1) for most of the analytes tested), with a precision in the range of 15%, fit-for-purpose for clinical control analysis.