Citations

Background: Cerebral microbleeds (CMBs) are a common vascular pathology associated with future intracerebral hemorrhage. Plasma biomarkers of amyloid, tau, and neurodegeneration may provide a screening avenue to identify those with CMBs, but evidence is conflicting. Objective: To determine the association between plasma biomarkers (Aβ40, Aβ42, t-tau, p-tau181, p-tau217, neurofilament light chain (NfL)) and CMBs in a population-based study of aging and whether these biomarkers predict higher signal on Aβ-PET imaging in patients with multiple CMBs. Methods: 712 participants from the Mayo Clinic Study of Aging with T2* GRE MRI and plasma biomarkers were included. Biomarkers were analyzed utilizing Simoa (Aβ40, Aβ42, t-tau, NfL) or Meso Scale Discovery (p-tau181, p-tau217) platforms. Cross-sectional associations between CMBs, plasma biomarkers and Aβ-PET were evaluated using hurdle models and multivariable regression models. Results: Among the 188 (26%) individuals with≥1 CMB, a lower plasma Aβ42/Aβ40 ratio was associated with more CMBs after adjusting for covariables (IRR 568.5 95% CI 2.8–116,127). No other biomarkers were associated with risk or number CMBs. In 81 individuals with≥2 CMBs, higher plasma t-tau, p-tau181, and p-tau217 all were associated with higher Aβ-PET signal, with plasma p-tau217 having the strongest predictive value (r2 0.603, AIC –53.0). Conclusion: Lower plasma Aβ42/Aβ40 ratio and higher plasma p-tau217 were associated with brain amyloidosis in individuals with CMBs from the general population. Our results suggest that in individuals with multiple CMBs and/or lobar intracranial hemorrhage that a lower plasma Aβ42/Aβ40 ratio or elevated p-tau217 may indicate underlying cerebral amyloid angiopathy.

Abstract Background Multiple sclerosis (MS) is an immune-mediated central nervous system (CNS) inflammatory demyelinating disease in which analysis of clinical presentation, imaging studies, and laboratory tests aid in diagnosis. Content This review discusses laboratory tests ordered to rule out and rule in MS, such as the traditional measurement of cerebrospinal fluid (CSF) IgG index and oligoclonal bands. Biomarkers discovered in the past 2 decades, such as aquaporin-4 (AQP4) antibodies and myelin oligodendrocyte glycoprotein (MOG) antibodies, have been incorporated into clinical practice in the diagnosis of disorders referred to as MS mimics. The importance of test selection, assay methodology, optimal sample for testing, and diagnostic utility of these biomarkers is reviewed. Other laboratory testing that can aid in the differentiation between MS and these biomarker-defined CNS demyelinating diseases is described. There is a focus on emerging biomarkers such as the use of kappa immunoglobulin free light chain concentration in CSF and kappa CSF index measurement as an alternative to oligoclonal bands which has a potential for an improvement in laboratory workflows. Finally, the role of biomarkers of disease activity and prognosis are discussed, including neurofilament light chain, glial fibrillary acidic protein, and myelin basic protein. Future perspectives with improved laboratory testing tools and discovery of additional biomarkers are provided. Summary Laboratory testing for demyelinating disorders using CSF and serum are routine practices that can benefit from an update, as novel biomarker-defined entities have reduced the potential for MS misdiagnosis, and CSF/serum biomarkers reinstated in the diagnostic criteria of MS.

Abstract Introduction : Plasma glial fibrillary acidic protein (GFAP) may be associated with amyloid burden, neurodegeneration, and stroke but its specificity for Alzheimer's disease (AD) in the general population is unclear. We examined associations of plasma GFAP with amyloid and tau positron emission tomography (PET), cortical thickness, white matter hyperintensities (WMH), and cerebral microbleeds (CMBs). Methods : The study included 200 individuals from the Mayo Clinic Study of Aging who underwent amyloid and tau PET and magnetic resonance imaging and had plasma GFAP concurrently assayed; multiple linear regression and hurdle model analyses were used to investigate associations controlling for age and sex. Results : GFAP was associated with amyloid and tau PET in multivariable models. After adjusting for amyloid, the association with tau PET was no longer significant. GFAP was associated with cortical thickness, WMH, and lobar CMBs only among those who were amyloid‐positive. Discussion : This cross‐sectional analysis demonstrates the utility of GFAP as a plasma biomarker for AD‐related pathologies.

AbstractBackgroundBlood‐based biomarkers of amyloid pathology and neurodegeneration are entering clinical use. It is critical to understand what factors affect these plasma marker levels for accurate clinical interpretation. Herein we examined factors associated with plasma Ab42, Ab40, neurofilament light (NfL), total tau (T‐tau), and the ratio of Ab42 to Ab40 (Ab42/40).MethodThe plasma markers were measured for 996 participants (859 cognitively unimpaired [CU], 133 mild cognitive impairment [MCI], 4 dementia) from the Mayo Clinic Study of Aging (MCSA), aged 51 to 95 years. The Quanterix Simoa® HD‐1 analyzer was employed to measure the plasma markers using the Simoa® Neurology 3‐Plex A (N3PA) (T‐tau, Ab42, Ab40) (catalog #101995) and the Simoa® NF‐light (catalog #103180). All other data was collected during in‐person MCSA visits or abstracted from the medical record. Statistical significance was determined using an alpha level of 0.05.ResultAmong CU, all of the plasma markers showed correlation with age. T‐tau (Spearman’s rho = 0.113, p<0.001) showed the weakest correlation and NfL (rho = 0.695, p<0.001) had the strongest. Women had higher levels of T‐tau (Median women: 2.782 vs. 2.390, p<0.001) and lower Ab42/40 (0.033 vs. 0.035, p=0.024) compared to men. In linear regression models predicting z‐scored plasma markers and adjusted for age and sex, several statistically significant predictors were found. For example, higher Charlson comorbidity index and chronic kidney disease were associated with higher levels of all markers; slower gait speed was associated with higher levels for all but Ab42/40 where no relationship was seen. A higher BMI was associated with higher levels of Ab42, Ab40, and T‐tau whereas NfL tended to be lower with increased BMI. Among participants with MCI or dementia, the relationship between gait speed or chronic kidney disease with NfL and T‐tau strengthened considerably.ConclusionMultiple variables affect plasma markers of amyloid pathology and neurodegeneration among CU in the general population. Some relationships differed among MCI and dementia participants. Incorporating this information is critical for accurate interpretation of the marker levels and for the development of reference ranges.

AbstractBackgroundDecreased amyloid β1‐42 (Aβ42) and increased tau (t‐Tau and p‐Tau) concentrations in cerebrospinal fluid (CSF) reflect the pathological changes of Alzheimer’s disease (AD) and aid in the diagnosis of AD dementia. In the United States, the ADmark® assay has been almost exclusively used for the measurement of these biomarkers in clinical practice. Recently, our institution switched from the ADmark® assay to the Roche Elecsys assays. The goal of this study was to determine if differences exist between these methods in classification of patients as having changes indicative of AD pathology.MethodPatients undergoing ADMark® testing (n= 73) were recruited to participate in this IRB‐approved study. Two simultaneous CSF aliquots were obtained. For ADMark®, 2.0mL were collected into a 5mL polypropylene (PP) tube and shipped frozen to Athena Diagnostics per collection instructions for testing (Innotest® immunoassays for Aβ42, t‐Tau, and p‐Tau). For the Roche Elecsys assays (Aβ42, t‐Tau, and p‐Tau), 2.0mL were collected into a 2.5mL low bind PP tube, frozen, and then tested at Mayo Clinic Laboratories. Comparative analysis was performed between the two testing methodologies and to clinical findings.ResultOverall concordance between the ADMark® Aβ42/t‐Tau index (ATI) and Roche p‐Tau/Aβ42 was 89% with 8 (11%) discrepant cases. Four cases were classified as normal by the Roche p‐Tau/Aβ42 but borderline (n=3) or abnormal (n=1) by ADMark® ATI. Four cases were classified as abnormal by the Roche p‐Tau/Aβ42 and borderline by ADMark® ATI. In these cases, the normal Roche p‐Tau/Aβ42 result was most consistent with clinical diagnosis. When compared to clinical diagnosis, cases with clinical suspicion of AD dementia were abnormal in 84% and 92% of cases with the ADMark® ATI and the Roche p‐Tau/Aβ42, respectively. In cases without clinical suspicion of AD dementia, results were abnormal in 19% and 21% of cases with the ADMark® ATI and the Roche p‐Tau/Aβ42, respectively. There were 2 cases with clinical suspicion of AD dementia and 5 cases without suspicion of AD dementia that were classified as borderline by ADMark® ATI.ConclusionRoche p‐Tau/Aβ42 showed comparable performance to ADMark® ATI when correlating results to clinical diagnosis of AD dementia.

Background: The syndrome of thyrotoxicosis typically relies on radioactive iodine scans for establishing its etiology. Alternatively, the determination of thyrotropin (TSH) receptor antibodies (TRAbs) helps to distinguish Graves' disease (GD) from thyrotoxic thyroiditis. Current assays are impacted by limitations in sensitivity and/or turnaround time. Therefore, we decided to test a new assay for the detection of TSH receptor stimulating antibodies (TSAbs) and compare it with the clinically available assays. Methods: We enrolled 110 individuals in 5 cohorts: patients with incident or recurrent GD (cohort 1); patients with thyroiditis, painless or subacute (cohort 2); patients with Graves' orbitopathy/thyroid eye disease (TED) in cohort 3; patients with Hashimoto's thyroiditis (cohort 4), and a control group of normal volunteers (cohort 5). The patients were tested with the two clinically available assays: Roche Elecsys anti-TSHR assay (ROC-TBII) from Roche Diagnostics and Thyretain™ TSI Reporter BioAssay Kit (QUI-TSI) from Quidel. In addition, the samples were tested with the aequorin TSAb assay (OTS-TSI) provided by Otsuka Pharmaceutical Co., Ltd. (Tokyo, Japan). The data were collected in a cross-sectional manner before initiation of therapy. Results: We had 36 cases of GD, 17 cases of thyroiditis, 27 cases of TED, 10 cases of Hashimoto's thyroiditis, and 20 normal volunteers. OTS-TSI had 100% sensitivity and specificity in distinguishing GD from thyroiditis, identical with QUI-TSI but superior to ROC-TBII (sensitivity 86% and specificity 94.1%). OTS-TSI had 93% sensitivity and 100% specificity for the diagnosis of TED, compared with normal controls. QUI-TSI and ROC-TBII performed similarly in this analysis, demonstrating 82% sensitivity and 100% specificity. The range of detectable values for OTS-TSI was 20–29,000 mIU/L and the turnaround time was ≤6 hours, without the need for cell culture equipment. Conclusions: OTS-TSI performed excellently, though similarly to QUI-TSI, for the differential diagnosis of GD vs. thyroiditis, while being superior in that respect to ROC-TBII. Furthermore, OTS-TSI has superior sensitivity to QUI-TSI and ROC-TBII for TED diagnosis, while retaining high specificity. It has a short turnaround time and avoids the need for cell culture and sterility. Larger studies in U.S. populations are needed for its validation.

AbstractIntroductionBlood‐based biomarkers of amyloid pathology and neurodegeneration are entering clinical use. It is critical to understand what factors affect the levels of these markers.MethodsPlasma markers (Aβ42, Aβ40, NfL, T‐tau, Aβ42/40 ratio) were measured on the Quanterix Simoa HD‐1 analyzer for 996 Mayo Clinic Study of Aging (MCSA) participants, aged 51 to 95 years. All other data were collected during in‐person MCSA visits or abstracted from the medical record.ResultsAmong cognitively unimpaired (CU) participants, all plasma markers correlated with age. Linear regression models revealed multiple relationships. For example, higher Charlson Comorbidity Index and chronic kidney disease were associated with higher levels of all biomarkers. Some relationships differed between mild cognitive impairment and dementia participants.DiscussionMultiple variables affect plasma biomarkers of amyloid pathology and neurodegeneration among CU in the general population. Incorporating this information is critical for accurate interpretation of the biomarker levels and for the development of reference ranges.

Abstract The Global Lab Quality Initiative (GLQI), formerly known as the Emerging Countries program, was funded through a generous endowment from the Wallace H. Coulter Foundation. The aims of GLQI are to develop and implement innovative programs to promote education and training in laboratory medicine for low- or lower middle-income countries worldwide. From its inception in 2010, the GLQI was focused solely on the Latin America and Caribbean (LAC) region under the purview of AACC’s Latin American Working Group (LAWG), the members of which have strong ties to the region thereby facilitating the partnerships with national societies. The LAWG has provided in-person workshops in the LAC countries, at the AACC Annual Scientific Meeting, and on-demand webinars. The LAWG aims to implement the GLQI aims in the LAC region. In-person workshops are based on best-practice recommendations and sources such as Clinical Laboratory Standard Institute guidelines and supplemented with professional experiences of the LAWG’s lecturers and local experts of the countries visited. In 2015, the GLQI expanded to other regions of the world. Here we report the experience of the LAWG workshops, results of participant surveys, in-person visits to laboratories post-workshop, and the lessons learned throughout the years across different geographic areas. We are hopeful this report provides insights into the challenges and successes of the LAWG in LAC to help support the expansion of the GLQI.

Abstract Objectives Assessment of surgical outcome in acromegaly is typically recommended at 3 to 6 months following surgery. The purpose of this study was to determine if insulin-like growth factor 1 (IGF-1) concentrations at 6 weeks were equally predictive of surgical outcomes compared with IGF-1 concentrations at 3 to 6 months postoperatively applying newer IGF-1 assays. Methods Retrospective review of patients with newly diagnosed acromegaly who had surgery between 2013 and 2020 and had postoperative IGF-1 measured by 6 weeks and 3 to 6 months. Results At 6 weeks, 20 (35%) of the total 57 had normal IGF-1 and became abnormal in 1 at 3 to 6 months, whereas 37 (65%) of 57 had abnormal IGF-1 concentrations at 6 weeks, which normalized in 1 patient by 3 to 6 months. In patients who changed clinical status, IGF-1 at 6 weeks was within ±0.1-fold of normal. Although a difference was seen between median IGF-1 concentrations (286 vs 267 ng/mL, P = .009) at 6 weeks and 3 to 6 months, the mean reduction was small (–19.9 ng/mL). Conclusions Compared with 3 to 6 months, use of IGF-1 at 6 weeks was associated with a change in clinical status in 3.5% of patients. Therefore, in most patients, IGF-1 at 6 weeks can be used to assess clinical outcome via newer assays.