Transthyretin monomers: a new plasma biomarker for pre-symptomatic transthyretin-related amyloidosis.

BACKGROUND: Genotyping and amyloid fibril detection in tissues are generally considered the diagnostic gold standard in transthyretin-related amyloidosis. Patients carry less stable TTR homotetramers prone to dissociation into non-native monomers, which rapidly self-assemble into oligomers and, ultimately, amyloid fibrils. Thus, the initial event of the amyloid cascade produces the smallest transthyretin species: the monomers. This creates engineering opportunities for diagnosis that remain unexplored. METHODS: We hypothesise that molecular sieving represents a promising method for isolating and concentrating trace TTR monomers from the tetramers present in plasma samples. Subsequently, immunodetection can be utilised to distinguish monomeric TTR from other low molecular weight proteins within the adsorbed fraction. A two-step assay was devised (ImmunoSieve assay), combining molecular sieving and immunodetection for sensing monomeric transthyretin. This assay was employed to analyse plasma microsamples from 10 individuals, including 5 pre-symptomatic carriers of TTR-V30M, the most prevalent amyloidosis-associated TTR variant worldwide, and 5 healthy controls. RESULTS: The ImmunoSieve assay enable sensitive detection of monomeric transthyretin in plasma microsamples. Moreover, the circulating monomeric TTR levels were significantly higher in carriers of amyloidogenic TTR mutation. CONCLUSIONS: Monomeric TTR can function as a biomarker for evaluating disease progression and assessing responses to therapies targeted at stabilising native TTR.

Serum amyloid A1 and pregnancy zone protein in pregnancy complications and correlation with markers of placental dysfunction.

BACKGROUND: Hypertensive disorders of pregnancy (preeclampsia, gestational hypertension, and chronic hypertension), diabetes mellitus, and placental dysfunction confer an increased risk of long-term maternal cardiovascular disease. Preeclampsia is also associated with acute atherosis that involves lesions of uteroplacental spiral arteries, resembling early stages of atherosclerosis. Serum amyloid A1 is involved in hypercoagulability and atherosclerosis and may aggregate into amyloid-aggregations of misfolded proteins. Pregnancy zone protein may inhibit amyloid aggregation. Amyloid is involved in Alzheimer's disease and cardiovascular disease; it has been identified in preeclampsia, but its role in preeclampsia pathophysiology is unclear. OBJECTIVE: We hypothesized that serum amyloid A1 would be increased and pregnancy zone protein decreased in hypertensive disorders of pregnancy and diabetic pregnancies and that serum amyloid A1 and pregnancy zone protein would correlate with placental dysfunction markers (fetal growth restriction and dysregulated angiogenic biomarkers) and acute atherosis. STUDY DESIGN: Serum amyloid A1 is measurable in both the serum and plasma. In our study, plasma from 549 pregnancies (normotensive, euglycemic controls: 258; early-onset preeclampsia: 71; late-onset preeclampsia: 98; gestational hypertension: 30; chronic hypertension: 9; diabetes mellitus: 83) was assayed for serum amyloid A1 and pregnancy zone protein. The serum levels of angiogenic biomarkers soluble fms-like tyrosine kinase-1 and placental growth factor were available for 547 pregnancies, and the results of acute atherosis evaluation were available for 313 pregnancies. The clinical characteristics and circulating biomarkers were compared between the pregnancy groups using the Mann-Whitney U, chi-squared, or Fisher exact test as appropriate. Spearman's rho was calculated for assessing correlations. RESULTS: In early-onset preeclampsia, serum amyloid A1 was increased compared with controls (17.1 vs 5.1 µg/mL, P<.001), whereas pregnancy zone protein was decreased (590 vs 892 µg/mL, P=.002). Pregnancy zone protein was also decreased in diabetes compared with controls (683 vs 892 µg/mL, P=.01). Serum amyloid A1 was associated with placental dysfunction (fetal growth restriction, elevated soluble fms-like tyrosine kinase-1 to placental growth factor ratio). Pregnancy zone protein correlated negatively with soluble fms-like tyrosine kinase-1 to placental growth factor ratio in all study groups. Acute atherosis was not associated with serum amyloid A1 or pregnancy zone protein. CONCLUSION: Proteins involved in atherosclerosis, hypercoagulability, and protein misfolding are dysregulated in early-onset preeclampsia and placental dysfunction, which links them and potentially contributes to future maternal cardiovascular disease.

Plasma Amyloid and in vivo Brain Amyloid in Late Middle-Aged Hispanics.

BACKGROUND: Determining amyloid positivity is possible with cerebrospinal fluid and brain imaging of amyloid, but these methods are invasive and expensive. OBJECTIVE: To relate plasma amyloid-ß (Aß), measured using Single-molecule array (Simoatrademark) assays, to in vivo brain Aß, measured using positron emission tomography (PET), examine the accuracy of plasma Aß to predict brain Aß positivity, and the relation of APOE ɛ4 with plasma Aß. METHODS: We performed a cross-sectional analysis in a cohort of 345 late middle-aged Hispanic men and women (age 64 years, 72% women). Our primary plasma variable was Aß42/Aß40 ratio measured with Simoa. Brain Aß burden was measured as global SUVR with 18F-Florbetaben PET examined continuously and categorically. RESULTS: Plasma Aß42/Aß40 ratio was inversely associated with global Aß SUVR (ß= -0.13, 95% Confidence Interval (CI): -0.23, -0.03; p = 0.013) and Aß positivity (Odds Ratio: 0.59, 95% CI: 0.38, 0.91; p = 0.016), independent of demographics and APOE ɛ4. ROC curves (AUC = 0.73, 95% CI: 0.64, 0.82; p < 0.0001) showed that the optimal threshold for plasma Aß42/Aß40 ratio in relation to brain Aß positivity was 0.060 with a sensitivity of 82.4% and specificity of 62.8%. APOE ɛ4 carriers had lower Aß42/Aß40 ratio and a higher Aß positivity determined with the Aß42/Aß40 ratio threshold of 0.060. CONCLUSION: Plasma Aß42/Aß40 ratio assayed using Simoa is weakly correlated with in vivo brain amyloid and has limited accuracy in screening for amyloid positivity and for studying risk factors of brain amyloid burden when in vivo imaging is not feasible.

A central role for amyloid fibrin microclots in long COVID/PASC: origins and therapeutic implications.

Post-acute sequelae of COVID (PASC), usually referred to as 'Long COVID' (a phenotype of COVID-19), is a relatively frequent consequence of SARS-CoV-2 infection, in which symptoms such as breathlessness, fatigue, 'brain fog', tissue damage, inflammation, and coagulopathies (dysfunctions of the blood coagulation system) persist long after the initial infection. It bears similarities to other post-viral syndromes, and to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Many regulatory health bodies still do not recognize this syndrome as a separate disease entity, and refer to it under the broad terminology of 'COVID', although its demographics are quite different from those of acute COVID-19. A few years ago, we discovered that fibrinogen in blood can clot into an anomalous 'amyloid' form of fibrin that (like other ß-rich amyloids and prions) is relatively resistant to proteolysis (fibrinolysis). The result, as is strongly manifested in platelet-poor plasma (PPP) of individuals with Long COVID, is extensive fibrin amyloid microclots that can persist, can entrap other proteins, and that may lead to the production of various autoantibodies. These microclots are more-or-less easily measured in PPP with the stain thioflavin T and a simple fluorescence microscope. Although the symptoms of Long COVID are multifarious, we here argue that the ability of these fibrin amyloid microclots (fibrinaloids) to block up capillaries, and thus to limit the passage of red blood cells and hence O2 exchange, can actually underpin the majority of these symptoms. Consistent with this, in a preliminary report, it has been shown that suitable and closely monitored 'triple' anticoagulant therapy that leads to the removal of the microclots also removes the other symptoms. Fibrin amyloid microclots represent a novel and potentially important target for both the understanding and treatment of Long COVID and related disorders.

Controllable signal molecule release from Au NP-gated MSNs for photocathodic detection of ultralow level AßO.

By integrating a target-responsive MSN-based controlled release system with a sensitization-SPR co-enhanced thionine/MoS2 QDs/Cu NWs photocathode, a highly sensitive split-type PEC aptasensing platform for AßO detection in blood is constructed. Ultralow detection limit (2.1 fM) and high selectivity show great potential in early AD diagnosis.

Biomarkers in AL Amyloidosis.

Systemic AL amyloidosis is a rare complex hematological disorder caused by clonal plasma cells which produce amyloidogenic immunoglobulins. Outcome and prognosis is the combinatory result of the extent and pattern of organ involvement secondary to amyloid fibril deposition and the biology and burden of the underlying plasma cell clone. Prognosis, as assessed by overall survival, and early outcomes is determined by degree of cardiac dysfunction and current staging systems are based on biomarkers that reflect the degree of cardiac damage. The risk of progression to end-stage renal disease requiring dialysis is assessed by renal staging systems. Longer-term survival and response to treatment is affected by markers of the underlying plasma cell clone; the genetic background of the clonal disease as evaluated by interphase fluorescence in situ hybridization in particular has predictive value and may guide treatment selection. Free light chain assessment forms the basis of hematological response criteria and minimal residual disease as assessed by sensitive methods is gradually being incorporated into clinical practice. However, sensitive biomarkers that could aid in the early diagnosis and that could reflect all aspects of organ damage and disease biology are needed and efforts to identify them are continuous.

Plasma amyloid ß levels are driven by genetic variants near APOE, BACE1, APP, PSEN2: A genome-wide association study in over 12,000 non-demented participants.

INTRODUCTION: There is increasing interest in plasma amyloid beta (Aß) as an endophenotype of Alzheimer's disease (AD). Identifying the genetic determinants of plasma Aß levels may elucidate important biological processes that determine plasma Aß measures. METHODS: We included 12,369 non-demented participants from eight population-based studies. Imputed genetic data and measured plasma Aß1-40, Aß1-42 levels and Aß1-42/Aß1-40 ratio were used to perform genome-wide association studies, and gene-based and pathway analyses. Significant variants and genes were followed up for their association with brain positron emission tomography Aß deposition and AD risk. RESULTS: Single-variant analysis identified associations with apolipoprotein E (APOE) for Aß1-42 and Aß1-42/Aß1-40 ratio, and BACE1 for Aß1-40. Gene-based analysis of Aß1-40 additionally identified associations for APP, PSEN2, CCK, and ZNF397. There was suggestive evidence for interaction between a BACE1 variant and APOE ε4 on brain Aß deposition. DISCUSSION: Identification of variants near/in known major Aß-processing genes strengthens the relevance of plasma-Aß levels as an endophenotype of AD.

Cerebrospinal Fluid Inflammatory Markers in Alzheimer's Disease: Influence of Comorbidities.

BACKGROUND: Alzheimer's disease (AD) develops into dementia after several years, and subjective cognitive impairment (SCI) and mild cognitive impairment (MCI) are used as intermediary diagnoses of increasing severity. Inflammation is an important part of AD pathology and provides potential novel biomarkers and treatment targets. OBJECTIVE: To identify novel potential biomarkers of AD in cerebrospinal fluid (CSF) and create a molecular pattern of inflammatory factors providing differentiation between AD and SCI. METHODS: We analyzed 43 inflammatory-related mediators in CSF samples from a cohort of SCI and AD cases vetted for confounding factors (Training cohort). Using multivariate analysis (MVA), a model for discrimination between SCI and AD was produced, which we then applied to a larger nonvetted cohort (named Test cohort). The data were analyzed for factors showing differences between diagnostic groups and factors that differed between the vetted and non-vetted cohorts. The relationship of the factors to the agreement between model and clinical diagnosis was investigated. RESULTS: A good MVA model able to discriminate AD from SCI without including tangle and plaque biomarkers was produced from the Training cohort. The model showed 50% agreement with clinical diagnosis in the Test cohort. Comparison of the cohorts indicated different patterns of factors distinguishing SCI from AD. As an example, soluble interleukin (IL)-6Rα showed lower levels in AD cases in the Training cohort, whereas placental growth factor (PlGF) and serum amyloid A (SAA) levels were higher in AD cases of the Test cohort. The levels of p-tau were also higher in the Training cohort. CONCLUSION: This study provides new knowledge regarding the involvement of inflammation in AD by indicating different patterns of factors in CSF depending on whether potential confounding comorbidities are present or not, and presents sIL-6Rα as a potential new biomarker for improved diagnosis of AD.

Blinded potency comparison of transthyretin kinetic stabilisers by subunit exchange in human plasma.

Transthyretin (TTR) tetramer dissociation is rate limiting for aggregation and subunit exchange. Slowing of TTR tetramer dissociation via kinetic stabiliser binding slows cardiomyopathy progression. Quadruplicate subunit exchange comparisons of the drug candidate AG10, and the drugs tolcapone, diflunisal, and tafamidis were carried out at 1, 5, 10, 20 and 30 µM concentrations in 4 distinct pooled wild type TTR (TTRwt) human plasma samples. These experiments reveal that the concentration dependence of the efficacy of each compound at inhibiting TTR dissociation was primarily determined by the ratio between the stabiliser's dissociation constants from TTR and albumin, which competes with TTR to bind kinetic stabilisers. The best stabilisers, tafamidis (80 mg QD), AG10 (800 mg BID), and tolcapone (3 x 100 mg over 12 h), exhibit very similar kinetic stabilisation at the plasma concentrations resulting from these doses. At a 10 µM plasma concentration, AG10 is slightly more potent as a kinetic stabiliser vs. tolcapone and tafamidis (which are similar), which are substantially more potent than diflunisal. Dissociation of TTR can be limited to 10% of its normal rate at concentrations of 5.7 µM AG10, 10.3 µM tolcapone, 12.0 µM tafamidis, and 188 µM diflunisal. The potency similarities revealed by our study suggest that differences in safety, adsorption and metabolism, pharmacokinetics, and tissue distribution become important for kinetic stabiliser clinical use decisions.

Neurofilament light chain, a biomarker for polyneuropathy in systemic amyloidosis.

OBJECTIVE: To study serum neurofilament light chain (sNfL) in amyloid light chain (AL) amyloidosis patients with and without polyneuropathy (PNP) and to corroborate previous observations that sNfL is increased in hereditary transthyretin-related (ATTRv) amyloidosis patients with PNP. METHODS: sNfL levels were assessed retrospectively in patients with AL amyloidosis with and without PNP (AL/PNP+ and AL/PNP-, respectively), patients with ATTRv amyloidosis and PNP (ATTRv/PNP+), asymptomatic transthyretin (TTR) gene mutation carriers (TTRv carriers) and healthy controls. Healthy controls (HC) were age- and sex-matched to both AL/PNP- (HC/AL) and TTRv carriers (HC/TTRv). The single-molecule array (Simoa) assay was used to assess sNfL levels. RESULTS: sNfL levels were increased both in 10 AL/PNP+ patients (p < .001) and in 10 AL/PNP- patients (p < .005) compared to 10 HC/AL individuals. sNfL levels were higher in AL/PNP+ patients than in AL/PNP- patients (p < .005). sNfL levels were also increased in 15 ATTRv/PNP+ patients, compared to both 15 HC/TTRv (p < .0001) and 15 TTRv carriers (p < .0001). ATTRv/PNP+ patients with progressive PNP (PND-score > I) had the highest sNfL levels compared to patients with early PNP (PND-score I) (p = .05). sNfL levels did not differ between TTRv carriers and HC/TTRv individuals. In the group comprising all healthy controls and in the group of TTRv carriers, sNfL levels correlated with age. CONCLUSION: sNfL levels are increased in patients with PNP in both AL and ATTRv amyloidosis and are related to severity of PNP in ATTRv amyloidosis. sNfL is a promising biomarker to detect PNP, not only in ATTRv but also in AL amyloidosis.

Prevalence of readily detected amyloid blood clots in 'unclotted' Type 2 Diabetes Mellitus and COVID-19 plasma: a preliminary report.

BACKGROUND: Type 2 Diabetes Mellitus (T2DM) is a well-known comorbidity to COVID-19 and coagulopathies are a common accompaniment to both T2DM and COVID-19. In addition, patients with COVID-19 are known to develop micro-clots within the lungs. The rapid detection of COVID-19 uses genotypic testing for the presence of SARS-Cov-2 virus in nasopharyngeal swabs, but it can have a poor sensitivity. A rapid, host-based physiological test that indicated clotting severity and the extent of clotting pathologies in the individual who was infected or not would be highly desirable. METHODS: Platelet poor plasma (PPP) was collected and frozen. On the day of analysis, PPP samples were thawed and analysed. We show here that microclots can be detected in the native plasma of twenty COVID-19, as well as ten T2DM patients, without the addition of any clotting agent, and in particular that such clots are amyloid in nature as judged by a standard fluorogenic stain. Results were compared to ten healthy age-matched individuals. RESULTS: In COVID-19 plasma these microclots are significantly increased when compared to the levels in T2DM. CONCLUSIONS: This fluorogenic test may provide a rapid and convenient test with 100% sensitivity (P < 0.0001) and is consistent with the recognition that the early detection and prevention of such clotting can have an important role in therapy.

Effect of Daily Intake of Green Tea Catechins on Cognitive Function in Middle-Aged and Older Subjects: A Randomized, Placebo-Controlled Study.

Epidemiological studies in Japan, including the Nakajima study and the Tsurugaya study, have indicated that green tea consumption may improve cognitive impairment. Catechins, which are typical polyphenols contained in green tea, have been reported to have antioxidative, anti-inflammatory, and neuroprotective effects. However, their impact on human cognitive function remains unclear. Therefore, we performed a double-blind, randomized, controlled study to investigate the effect of 336.4 mg of decaffeinated green tea catechins (GTC) on cognitive function after a single dose and after 12 weeks of daily intake. This study included Japanese adults between the ages of 50 and 69 years with a Mini-Mental State Examination Japanese version score of >24 and self-assessed cognitive decline. The Cognitrax testing battery was used to evaluate cognitive function. The incorrect response rate on the Continuous Performance Test significantly decreased after a single dose of GTC. After 12 weeks of daily GTC intake, the response time for Part 4 of the 4-part Continuous Performance Test, which is a two-back test, was shortened. These results suggest that daily intake of GTC might have beneficial effects on working memory.

Advancing medicine for Alzheimer's disease: A plasma neural exosome platform.

Enrichment of neurally derived extracellular vesicles of several cell-types from plasma for protein quantification longitudinally in living patients with Alzheimer's disease has permitted the development of a tentative temporal framework of initiating events, progression mechanisms, and amplification processes. Interactions of beta-amyloid peptides with an elevated level of their normal prion protein dendritic receptor and of phospho-tau species with their synaptogyrin-3 synaptic vesicle receptor replace excessive production and accumulation of neuropathic proteins as the major initiating events. Synaptic dysfunction and microvascular angiopathy are confirmed as early progression mechanisms of decreased neuronal network connectivity, hypoxia, altered blood-brain barrier, and neurocellular degeneration. Neurally derived extracellular vesicle protein abnormalities also reveal a range of later amplification processes that encompasses insulin resistance, lysosomal defects, decreased survival factors, increased reactive oxygen species, and excessive neuroinflammation. New potential therapeutic targets also are suggested as well as the likely timing of their pathogenic engagement.

Total Aß42/Aß40 ratio in plasma predicts amyloid-PET status, independent of clinical AD diagnosis.

OBJECTIVE: To explore whether the plasma total ß-amyloid (Aß) Aß42/Aß40 ratio is a reliable predictor of the amyloid-PET status by exploring the association between these 2 variables in a subset of the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging cohort. METHODS: Taking plasma samples at 3 separate time points, month 18 (n = 176), month 36 (n = 169), and month 54 (n = 135), we assessed the total Aß42/Aß40 ratio in plasma (TP42/40) with regard to neocortical Aß burden via PET standardized uptake value ratio (SUVR) and investigated both association with Aß-PET status and correlation (and agreement) with SUVR. RESULTS: The TP42/40 plasma ratio was significantly reduced in amyloid-PET-positive participants at all time points (p < 0.0001). Adjusting for covariates age, gender, APOE ε4 allele status, and clinical classification clearly affects the significance, with p values reduced and only comparisons at 54 months retaining significance (p = 0.006). Correlations with SUVR were similar across each time point, with Spearman ρ reaching -0.64 (p < 0.0001). Area under the curve values were highly reproducible over time points, with values ranging from 0.880 at 36 months to 0.913 at 54 months. In assessments of the healthy control group only, the same relationships were found. CONCLUSIONS: The current study demonstrates reproducibility of the plasma assay to discriminate between amyloid-PET positive and negative over 3 time points, which can help to substantially reducing the screening rate of failure for clinical trials targeting preclinical or prodromal disease. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that plasma total Aß42/Aß40 ratio is associated with neocortical amyloid burden as measured by PET SUVR.

One-carbon metabolites, B vitamins and associations with systemic inflammation and angiogenesis biomarkers among colorectal cancer patients: results from the ColoCare Study.

B vitamins involved in one-carbon metabolism have been implicated in the development of inflammation- and angiogenesis-related chronic diseases, such as colorectal cancer (CRC). Yet, the role of one-carbon metabolism in inflammation and angiogenesis among CRC patients remains unclear. The objective of this study was to investigate associations of components of one-carbon metabolism with inflammation and angiogenesis biomarkers among newly diagnosed CRC patients (n 238) in the prospective ColoCare Study, Heidelberg. We cross-sectionally analysed associations between twelve B vitamins and one-carbon metabolites and ten inflammation and angiogenesis biomarkers from pre-surgery serum samples using multivariable linear regression models. We further explored associations among novel biomarkers in these pathways with Spearman partial correlation analyses. We hypothesised that pyridoxal-5'-phosphate (PLP) is inversely associated with inflammatory biomarkers. We observed that PLP was inversely associated with C-reactive protein (CRP) (r -0·33, Plinear < 0·0001), serum amyloid A (SAA) (r -0·23, Plinear = 0·003), IL-6 (r -0·39, Plinear < 0·0001), IL-8 (r -0·20, Plinear = 0·02) and TNFα (r -0·12, Plinear = 0·045). Similar findings were observed for 5-methyl-tetrahydrofolate and CRP (r -0·14), SAA (r -0·14) and TNFα (r -0·15) among CRC patients. Folate catabolite acetyl-para-aminobenzoylglutamic acid (pABG) was positively correlated with IL-6 (r 0·27, Plinear < 0·0001), and pABG was positively correlated with IL-8 (r 0·21, Plinear < 0·0001), indicating higher folate utilisation during inflammation. Our data support the hypothesis of inverse associations between PLP and inflammatory biomarkers among CRC patients. A better understanding of the role and inter-relation of PLP and other one-carbon metabolites with inflammatory processes among colorectal carcinogenesis and prognosis could identify targets for future dietary guidance for CRC patients.

Serum amyloid A: A potential biomarker of lung disorders.

Serum amyloid A is an acute-phase protein with multiple immunological functions. Serum amyloid A is involved in lipid metabolism, inflammatory reactions, granuloma formation, and cancerogenesis. Additionally, serum amyloid A is involved in the pathogenesis of different autoimmune lung diseases. The levels of serum amyloid A has been evaluated in biological fluids of patients with different lung diseases, including autoimmune disorders, chronic obstructive pulmonary diseases, obstructive sleep apnea syndrome, sarcoidosis, asthma, lung cancer, and other lung disorders, such as idiopathic pulmonary fibrosis, tuberculosis, radiation pneumonitis, and cystic fibrosis. This review focuses on the cellular and molecular interactions of serum amyloid A in different lung diseases and suggests this acute-phase protein as a prognostic marker.

Beneficial Effect of Pimobendan for Severe Heart Failure Due to Transthyretin Cardiac Amyloidosis.

Objective Transthyretin amyloidosis, particularly wild-type transthyretin amyloid cardiomyopathy (ATTRwt), has been recognized as an important cause of morbidity and mortality in the aging population. However, it is difficult to manage heart failure itself in patients with cardiac amyloidosis. Methods We herein report the management of heart failure in an elderly patient with severe heart failure due to ATTRwt. We also review the clinical situation in an additional seven patients with cardiac amyloidosis who were administered pimobendan in our hospital. Results We treated a 71-year-old man with refractory heart failure due to ATTRwt. He was expected to be dependent on dobutamine infusion. We administered pimobendan and successfully improved his symptoms and hemodynamic status to allow his discharge from the hospital. An additional retrospective investigation observed that there were eight patients with ATTR amyloidosis who were administered pimobendan. Although all of the patients at the time of administration of pimobendan were NYHA class III or IV with repeated hospitalization for heart failure, pimobendan seemed to be effective for improving symptoms and enabling patients to be discharged and receive outpatient medical care. Furthermore, focusing on the changes in some biomarkers, we found that the brain natriuretic peptide and estimated glomerular filtration rate values improved after the administration of pimobendan in 5 consecutive patients for whom data were available without additional treatment (p=0.018 and 0.051, respectively). Conclusion In clinical practice, pimobendan seems to have beneficial effects in heart failure management for improving physical activities and the quality of life in patients with transthyretin cardiac amyloidosis.

Plasma amyloid and tau as dementia biomarkers in Down syndrome: Systematic review and meta-analyses.

Individuals with Down syndrome (DS) are at high risk of developing Alzheimer's disease (AD). Discovering reliable biomarkers which could facilitate early AD diagnosis and be used to predict/monitor disease course would be extremely valuable. To examine if analytes in blood related to amyloid plaques may constitute such biomarkers, we conducted meta-analyses of studies comparing plasma amyloid beta (Aß) levels between DS individuals and controls, and between DS individuals with and without dementia. PubMed, Embase, and Google Scholar were searched for studies investigating the relationship between Aß plasma concentrations and dementia in DS and 10 studies collectively comprising >1,600 adults, including >1,400 individuals with DS, were included. RevMan 5.3 was used to perform meta-analyses. Meta-analyses showed higher plasma Aß40 (SMD = 1.79, 95% CI [1.14, 2.44], Z = 5.40, p < .00001) and plasma Aß42 levels (SMD = 1.41, 95% CI [1.15, 1.68], Z = 10.46, p < .00001) in DS individuals than controls, and revealed that DS individuals with dementia had higher plasma Aß40 levels (SMD = 0.23, 95% CI [0.05, 0.41], Z = 2.54, p = .01) and lower Aß42 /Aß40 ratios (SMD = -0.33, 95% CI [-0.63, -0.03], Z = 2.15, p = .03) than DS individuals without dementia. Our results indicate that plasma Aß40 levels may constitute a promising biomarker for predicting dementia status in individuals with DS. Further investigations using new ultra-sensitive assays are required to obtain more reliable results and to investigate to what extent these results may be generalizable beyond the DS population.

Serum amyloid A and muscle activity biomarkers in horses submitted to equestrian show jumping / Biomarcadores de amilóide sérica A e de atividade muscular em cavalos submetidos a salto equestre

The aim of this study was to evaluate the serum amyloid A (SAA) and biomarkers of muscle activity of horses submitted to show jumping activity. To do this, the variables SAA, glucose, lactate and the biomarkers creatine kinase (CK) and aspartate amino transferase (AST) were evaluated in 10 horses submitted to the show jumping exercise in a tournament for beginners. The evaluations occurred before exercise (T0), immediately after (T1), 30 minutes (T2), 60 minutes (T3) and 24 hours after the end (T4). Data were evaluated using analysis of variance for repeated measures. The statistical software SAEG 9.1 was used to verify the level of significance between the moments for P<0.05. Glucose presented a difference between the moments T0 (97.7±13.3mg/dL) and T1 (79.7±14.1mg/dL). Lactate presented elevation in T1 (15.3±6.1mmol/L) compared to the others T0 (3.8±0.8mmol/L), T2 (6.5±3.9mmol/L), T3 (5.3±2.2mmol/L) and T4 (5.1±1.6mmol/L). The CK showed a significant difference between T0 (82.8±51.2U/L) and T1 (140.1±58.5U/L) and between T4 (74.4±43.1U/L) with T1 (140.1±58.5U/L). The AST presented no difference between moments. The show jumping activity with one-meter obstacles did not induce changes in the SAA protein between the moments.(AU)

O objetivo deste estudo foi avaliar a amilóide sérica A (SAA) e biomarcadores de atividade muscular de equinos submetidos a atividade de salto, ou hipismo clássico. Para tanto, foram avaliadas as variáveis SAA, glicose, lactato e os biomarcadores creatina quinase (CK) e aspartatoaminotransferase (AST) em 10 equinos submetidos ao exercício de saltos em torneio para iniciantes. As avaliações ocorreram antes do exercício (T0), imediatamente após (T1), 30 minutos (T2), 60 minutos (T3) e 24 horas após o término (T4). Os dados foram avaliados utilizando análise de variância para medidas repetidas. O software estatístico SAEG 9.1 foi utilizado para verificar o nível de significância entre os momentos para P<0,05. A glicose diferenciou-se entre os momentos T0 (97.7±13.3mg/dL) e T1 (79.7±14.1mg/dL). O lactado apresentou elevação comparada com o momento T1(15.3±6.1mmol/L) e os demais T0 (3.8±0.8mmol/L), T2 (6.5±3.9mmol/L), T3 (5.3±2.2mmol/L) e T4 (5.1±1.6mmol/L). A CK mostrou diferença significativa entre T0 (82.8±51.2U/L) e T1 (140.1±58.5U/L) e entre T4 (74.4±43.1U/L) com T1 (140.1±58.5U/L). A AST não apresentou diferença entre os momentos. A atividade de hipismo clássico com obstáculos de um metro não induziu alterações na proteína SAA entre os momentos.(AU)