Association of thyroid autoimmune status with Alzheimer's disease biomarkers in euthyroid subjects.

Alzheimer's disease biomarkers are widely accepted as surrogate markers of underlying neuropathological changes. However, few studies have evaluated whether preclinical Alzheimer's disease biomarkers predict Alzheimer's neuropathology at autopsy. We sought to determine whether amyloid PET imaging or CSF biomarkers accurately predict cognitive outcomes and Alzheimer's disease neuropathological findings. This study included 720 participants, 42-91 years of age, who were enrolled in longitudinal studies of memory and aging in the Washington University Knight Alzheimer Disease Research Center and were cognitively normal at baseline, underwent amyloid PET imaging and/or CSF collection within 1 year of baseline clinical assessment, and had subsequent clinical follow-up. Cognitive status was assessed longitudinally by Clinical Dementia Rating®. Biomarker status was assessed using predefined cut-offs for amyloid PET imaging or CSF p-tau181/amyloid-β42. Subsequently, 57 participants died and underwent neuropathologic examination. Alzheimer's disease neuropathological changes were assessed using standard criteria. We assessed the predictive value of Alzheimer's disease biomarker status on progression to cognitive impairment and for presence of Alzheimer's disease neuropathological changes. Among cognitively normal participants with positive biomarkers, 34.4% developed cognitive impairment (Clinical Dementia Rating > 0) as compared to 8.4% of those with negative biomarkers. Cox proportional hazards modelling indicated that preclinical Alzheimer's disease biomarker status, APOE ɛ4 carrier status, polygenic risk score and centred age influenced risk of developing cognitive impairment. Among autopsied participants, 90.9% of biomarker-positive participants and 8.6% of biomarker-negative participants had Alzheimer's disease neuropathological changes. Sensitivity was 87.0%, specificity 94.1%, positive predictive value 90.9% and negative predictive value 91.4% for detection of Alzheimer's disease neuropathological changes by preclinical biomarkers. Single CSF and amyloid PET baseline biomarkers were also predictive of Alzheimer's disease neuropathological changes, as well as Thal phase and Braak stage of pathology at autopsy. Biomarker-negative participants who developed cognitive impairment were more likely to exhibit non-Alzheimer's disease pathology at autopsy. The detection of preclinical Alzheimer's disease biomarkers is strongly predictive of future cognitive impairment and accurately predicts presence of Alzheimer's disease neuropathology at autopsy.

A set of core cerebrospinal fluid (CSF) biomarkers for Alzheimer’s disease (AD) includes total tau (T-tau), phosphorylated tau (P-tau) and β-amyloid 42 (Aβ42). These biomarkers reflect some of the key aspects of AD pathophysiology, including neuronal degeneration, tau phosphorylation with tangle formation, and Aβ aggregation with deposition of the peptide into plaques. The core AD CSF biomarkers have been validated clinically in numerous studies, and found to have a very high diagnostic performance to identify AD, both in the dementia and in the mild cognitive impairment stages of the disease. CSF Aβ42 has also been found to show very high concordance with amyloid PET to identify brain amyloid deposition. The synaptic protein neurogranin is a novel candidate CSF biomarker for AD and prodromal AD. High CSF neurogranin predicts future cognitive decline and seems to be more specific for AD than, for example, T-tau. Importantly, technical developments have given ultrasensitive measurement techniques that allow measurement of brain-specific proteins such as tau and neurofilament light (NFL) in blood samples. Both plasma tau and NFL are increased in AD, and a recent study showed that plasma NFL has a diagnostic performance comparable to the core AD CSF biomarkers, and predicted future cognitive decline. Future large longitudinal clinical studies are warranted to determine the potential for plasma tau and NFL to serve as first-in-line screening tools for neurodegeneration in primary care.

Intense multidisciplinary research has provided detailed knowledge of the molecular pathogenesis of Alzheimer disease (AD). This knowledge has been translated into new therapeutic strategies with putative disease-modifying effects. Several of the most promising approaches, such as amyloid-beta immunotherapy and secretase inhibition, are now being tested in clinical trials. Disease-modifying treatments might be at their most effective when initiated very early in the course of AD, before amyloid plaques and neurodegeneration become too widespread. Thus, biomarkers are needed that can detect AD in the predementia phase or, ideally, in presymptomatic individuals. In this Review, we present the rationales behind and the diagnostic performances of the core cerebrospinal fluid (CSF) biomarkers for AD, namely total tau, phosphorylated tau and the 42 amino acid form of amyloid-beta. These biomarkers reflect AD pathology, and are candidate markers for predicting future cognitive decline in healthy individuals and the progression to dementia in patients who are cognitively impaired. We also discuss emerging plasma and CSF biomarkers, and explore new proteomics-based strategies for identifying additional CSF markers. Furthermore, we outline the roles of CSF biomarkers in drug discovery and clinical trials, and provide perspectives on AD biomarker discovery and the validation of such markers for use in the clinic.

More than half of neurodegenerative disease patients have multiple pathologies at autopsy; however, most receive one diagnosis during life. We used the α-synuclein seed amplification assay (αSyn-SAA) and CSF biomarkers for amyloidosis and Alzheimer's disease (AD) neuropathological change (ADNC) to determine the frequency of co-pathologies in participants clinically diagnosed with Lewy body (LB) disease or AD. Using receiver operating characteristic analyses on retrospective CSF samples from 150 participants determined αSyn-SAA accuracy, sensitivity, and specificity for identifying clinically defined LB disease and predicting future change in clinical diagnosis. CSF biomarkers helped determine the frequency of concomitant Lewy body pathology, ADNC, and/or amyloidosis in participants with LB disease and AD, across clinical spectra. Following a decade-long follow-up, the clinically or autopsy-defined diagnosis changed for nine participants. αSyn-SAA demonstrated improved accuracy (91.3%), sensitivity (89.3%), and specificity (93.3%) for identifying LB disease compared to all non-LB disease, highlighting the limitations of clinical diagnosis alone. When examining biomarkers of co-pathology, amyloidosis was present in 18%, 48%, and 71% (χ2(2) = 13.56, p = 0.001) and AD biomarkers were present in 0%, 8.7%, and 42.9% (χ2(2) = 18.44, p < 0.001) of LB disease participants with different stages of cognitive impairment respectively. Co-occurring biomarkers for αSyn-SAA and amyloidosis were present in 12% and 14% of AD compared to 43% and 57% LB disease participants with different stages of cognitive impairment (χ2(3) = 13.87, p = 0.003). Our study shows that using a combination of αSyn-SAA and AD biomarkers can identify people with αSyn, ADNC, and co-pathology better and earlier than traditional clinical diagnostic criteria alone.

Plasma p‐tau181, p‐tau217, and other blood‐based Alzheimer's disease biomarkers in a multi‐ethnic, community study

The core cerebrospinal fluid (CSF) biomarkers; total tau (tTau), phospho-tau (pTau), amyloid β1-42(Aβ 1-42), and the Aβ 1-42/Aβ 1-40 ratio have transformed Alzheimer's disease (AD) research and are today increasingly used in clinical routine laboratories as diagnostic tools. Fully automated immunoassay instruments with ready-to-use assay kits and calibrators has simplified their analysis and improved reproducibility of measurements. We evaluated the analytical performance of the fully automated immunoassay instrument LUMIPULSE G (Fujirebio) for measurement of the four core AD CSF biomarkers and determined cutpoints for AD diagnosis. Comparison of the LUMIPULSE G assays was performed with the established INNOTEST ELISAs (Fujirebio) for hTau Ag, pTau 181, β-amyloid 1-42, and with V-PLEX Plus Aβ Peptide Panel 1 (6E10) (Meso Scale Discovery) for Aβ 1-42/Aβ 1-40, as well as with a LC-MS reference method for Aβ 1-42. Intra- and inter-laboratory reproducibility was evaluated for all assays. Clinical cutpoints for Aβ 1-42, tTau, and pTau was determined by analysis of three cohorts of clinically diagnosed patients, comprising 651 CSF samples. For the Aβ 1-42/Aβ 1-40 ratio, the cutpoint was determined by mixture model analysis of 2,782 CSF samples. The LUMIPULSE G assays showed strong correlation to all other immunoassays (r>0.93 for all assays). The repeatability (intra-laboratory) CVs ranged between 2.0 and 5.6%, with the highest variation observed for β-amyloid 1-40. The reproducibility (inter-laboratory) CVs ranged between 2.1 and 6.5%, with the highest variation observed for β-amyloid 1-42. The clinical cutpoints for AD were determined to be 409ng/L for total tau, 50.2ng/L for pTau 181, 526ng/L for β-amyloid 1-42, and 0.072 for the Aβ 1-42/Aβ 1-40 ratio. Our results suggest that the LUMIPULSE G assays for the CSF AD biomarkers are fit for purpose in clinical laboratory practice. Further, they corroborate earlier presented reference limits for the biomarkers.

The aim of the present study was to explore the influence of positive simple thyroid peroxidase antibody (TPO-Ab) on female infertility. Venous blood was collected on an empty stomach from infertile female patients (all of whom were in line with the World Health Organization's diagnostic criteria for infertility) receiving treatments at The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University from 2014 to 2017 to detect thyroid function and thyroid antibodies [thyroglobulin antibody (TG-Ab), TPO-Ab and thyroid microsome antibody (TM-Ab)]. A total of 529 patients with normal thyroid function, TG-Ab and TM-Ab were included in the present study; they were divided into the positive group (121 cases with positive TPO-Ab) and the negative group (408 cases with negative TPO-Ab). Comparisons of age, body mass index (BMI), basal hormone levels, irregular menstruation, tubal obstruction, premature ovarian failure (POF), endometriosis (EMT) and polycystic ovary syndrome (PCOS) between the two groups of patients were conducted in order to determine whether the differences were statistically significant. The incidence rate of EMT was 39.6% in the positive group and 17.1% in the negative group (P<0.05). The incidence rate of PCOS in the observation group was 43.9%, which was significantly higher than that of the control group (21.3%; P<0.01). The results revealed that the differences in age, BMI, basal hormone levels, irregular menstruation and POF between the two groups were not statistically significant (P>0.05). Finally, the factors that had statistical significance (EMT and PCOS) were stratified by different age groups to compare the incidence rate of positive results among the different age groups, thus concluding which age group was influenced to a greater extent by TPO-Ab. The results indicated that positive TPO-Ab may be associated with PCOS and EMT, though particularly with PCOS. Infertile PCOS patients aged 28–35 years old were influenced more by TPO-Ab than those in other age groups. Thus, it is recommended that thyroid autoantibodies are detected in infertile PCOS females aged 28–35 years old, and treatment should be administered as soon thereafter.

The association between iodine intake and thyroid autoimmunity has been debated, especially in pregnant women. This study aimed to investigate thyroid autoantibodies and their association with iodine intake and hypothyroidism in early pregnancy. 7073 early pregnant women from an iodine-sufficient region participated in this study. Urinary iodine concentrations (UICs) were measured using an ammonium persulfate method. Serum thyroid peroxidase antibody (TPOAb), thyroglobulin antibody (TgAb), thyroid-stimulating hormone (TSH), free thyroxine (FT4), and Tg were determined using an electrochemiluminescence immunoassay. Iodine deficiency (UIC < 100μg/L) was associated with higher risks of TPOAb positivity [adjusted odds ratio (aOR) = 1.64, 95% confidence interval [CI] (1.29-2.08)] and TgAb positivity [aOR = 1.44, 95% CI (1.16-1.80)]. Women with isolated TPOAb positivity, isolated TgAb positivity, or both TPOAb and TgAb positivity had a 14.64-fold, 7.83-fold, and 44.69-fold increased risk of overt hypothyroidism, and a 4.36-fold, 2.86-fold, and 6.26-fold increased risk of subclinical hypothyroidism, respectively. Moreover, the risks of overt and subclinical hypothyroidism in women with a high TPOAb titer were 16.99 and 4.80 times that in TPOAb-negative women, respectively. The risk of overt hypothyroidism in women with a high TgAb titer was 6.97 times that in TgAb-negative women. Our work demonstrates that iodine deficiency during early pregnancy is an independent risk factor for both TPOAb positivity and TgAb positivity. Furthermore, positivity for both autoantibodies and a high thyroid autoantibody titer are associated with significantly higher risks of overt and subclinical hypothyroidism.

Background:Recently, the abnormal presence of thyroglobulin antibody (TG-Ab) and thyroid peroxidase antibody (TPO-Ab) has been reported in vitiligo patients, but presence of TG-Ab and TPO-Ab in patients of different ages and gender, and its association with vitiligo and thyroid autoimmunity has rarely been reported. The aim of our research was to determine whether vitiligo was associated with thyroid autoimmunity and figure out its relationship with age and gender.Materials and Methods:We analyzed TG-Ab, TPO-Ab in age and gender matched 87 vitiligo patients and 90 healthy controls, the patients of vitiligo who were positive for the presence of TG-Ab and TPO-Ab were followed up to confirm autoimmune thyroid disease subsequently.Results:Results showed that the frequencies of TG-Ab (23.0%, 20/87) positivity and TPO-AB (24.1%, 21/87) in vitiligo patients were significantly higher than that in healthy controls (P < 0.05). Moreover, The positivity for of TG-Ab and TPO-Ab was higher in 11-20-year age group and 21-40-year age group than that in age matched healthy controls. We found female patients with vitiligo had higher positive frequencies of TG-Ab and TPO-Ab than healthy female controls. (34.1% vs. 8.8% and 34.1% vs. 11.1%, P = 0.000 and P = 0.011). When 20 patients with TG-Ab and TPO-Ab positivity were followed up for three monthes, 14 of them (70%) were diagnosed as having autoimmune thyroid disease compared with age-matched healthy controls (16.7%, χ2 = 5.4, P = 0.02).Conclusion:TG-Ab and TPO-Ab are likely to be found in female teenagers with vitiligo, and are relevant with respect to subsequent development autoimmune thyroid disease.

The Alzheimer's association global quality control program for CSF biomarkers

Stroke risk interacts with Alzheimer's disease biomarkers on brain aging outcomes

Quantification of tau phosphorylated at threonine 217 using a novel ultrasensitive immunoassay distinguishes Alzheimer’s disease from healthy controls

Herpes simplex virus alters Alzheimer's disease biomarkers - A hypothesis paper.

The objective of this study was to examine the urinary iodine concentration (UIC)-thyroid autoimmunity (TAI) association and UIC-selenium intake interaction in U.S. adults. We analyzed 2007-2012 National Health and Nutrition Examination Survey (NHANES) data on ≥20-year-old adults (n = 6612). Their food and supplemental selenium intake was measured. The associations of the UIC and selenium intake with thyroid peroxidase antibody (TPOAb) positivity, thyroglobulin antibody (TgAb) positivity, and TAI were assessed via weighted multivariable logistic regression. Interaction and subgroup analyses were conducted. Nonlinear relationships were explored and visualized via restricted cubic splines (RCSs). Compared with a UIC 100~200 μg/L, a UIC 500~800 μg/L was associated with a 57% increased TPOAb positivity risk (OR = 1.57 [CI = 1.07-2.30]; p = 0.022), a one-fold greater TgAb positivity risk (OR = 2.00 [CI = 1.10-3.65]; p = 0.025), and a 62% increased TAI risk (OR = 1.62 [CI = 1.07-2.45]; p = 0.024). Nonlinear relationships between the UIC and thyroid antibody positivity were observed. According to the univariate models, each 1 μg increase in selenium intake was associated with a 0.049 IU/mL decrease in the TPOAb levels (β [95% CI] = -0.049 [-0.092--0.005]; p = 0.028). In the low-selenium group, a UIC of 200~300 μg/L was a risk factor for TPOAb positivity (p = 0.046). At a moderate level of selenium intake, a UIC of 300~800 μg/L significantly increased the TPOAb positivity risk (all p < 0.05). At a high level of selenium intake, the UIC and TPOAb positivity risks were not significantly associated (all p > 0.05). A UIC of 500~800 μg/L is an independent TAI risk factor. The selenium intake modifies the UIC-thyroid antibody positivity relationship, with the association disappearing at high selenium levels.

While screening of thyroid peroxidase antibody (TPOAb) has been recommended in women with primary ovarian insufficiency, the relationship between thyroid autoimmunity (TAI) and ovarian reserve remains undetermined. Because the TAI prevalence was reported to be different between different ethnic/racial groups, this study aimed to investigate the TAI prevalence in Chinese women with variable ovarian reserve. This is a cross-sectional study conducted in a university infertility clinic between October 2013 and March 2016. Among patients at their first entry to the infertility clinic, a total of 1044 patients with available results of anti-Müllerian hormone (AMH), thyrotropin (TSH), TPOAb, and thyroglobulin antibody (TgAb) were enrolled. The TSH levels and the prevalence of positive TPOAb and positive TgAb were compared between patients with low, normal, and high ovarian reserve categorized with age-specific AMH levels. For the whole study population, the TSH levels, TPOAb positivity, and TgAb positivity were comparable between patients with variable ovarian reserve. However, after patients with known causes compromising ovarian reserve (iatrogenic or genetic) were excluded, only TPOAb positivity became significantly different between patients with low (22.7%), normal (14.0%), and high ovarian reserve (10.3%; p = 0.012). The TPOAb levels were not significantly correlated to AMH levels (Spearman's ρ = -0.027; p = 0.413). For the infertile subgroup, TPOAb positivity was significantly associated with idiopathic low ovarian reserve in unexplained infertility (low ovarian reserve: 28.6%; normal: 15.7%; high: 9.5%; p = 0.020). Idiopathic low ovarian reserve was associated with more frequent positive TPOAb rather than thyroid function or TgAb positivity in Chinese women.