AA Amyloidosis Research Articles

Expert Center for cardiac amyloidosis: reality and perspectives

Aim. To evaluate the features of diagnosis of amyloid cardiomyopathy (ACMP), differential diagnosis of different types of amyloidosis and its clinical manifestations. Materials and methods. Were analyzed 150 cases of patients who consulted at the Expert Center for Amyloidosis with suspicion of the presence of ACMP. 63 patients were diagnosed with ACMP: 25 (39.7%) – women, 38 (60.3%) – men, with an average age of 64.1±1.5. 36 (57.1%) patients had AL-amyloidosis (immunoglobulin amyloid light-chain amyloidosis), 25 (39.7%) – ATTR-amyloidosis (transthyretin amyloidosis), 2 (3.2%) – AA-amyloidosis with heart failure (reactive systemic amyloidosis caused by hypersecretion of á-globulin). The analysis of clinical manifestations depending on the type of amyloidosis, data of laboratory and instrumental methods of diagnosis is carried out. Results. In most cases, 53 (84.1%) patients, amyloidosis manifested as signs of heart failure. Among cardiac manifestations, shortness of breath (95.2%), general weakness (93.7%), lower limb edema (76.2%) were the most common. To confirm the diagnosis, despite the high accuracy of the speckle-tracking echocardiography and magnetic resonance imaging of the heart with gadolinium, in rare cases a biopsy is required (e.g. there is a combination of clinical signs of several types of amyloidosis). Biopsy of the affected organ was performed in 31 (49.2%) patients. The strategy for further pathogenetic treatment depends on the determination of the type of amyloidosis. Free light chains of immunoglobulins were detected in 57.1% of cases, which allowed diagnosis of AL-amyloidosis. In 17 (38.6%) patients myocardial scintigraphy with 99mTc-pyrophosphate showed signs of ATTR-amyloidosis, which with a negative result of immunochemical studies allows non-invasive diagnosis of it. Conclusion. ACMP is a disease with an extremely adverse prognosis. Raising the awareness of specialists about ACMP is an important goal. With timely diagnosis, pathogenetic therapy can be started early, which will improve the quality of life and prognosis of patients with ACMP.

BDMARD can prevent the progression of AA amyloidosis to end-stage renal disease.

AA amyloidosis (AA) can be the consequence of any chronic inflammatory disease. AA is associated with chronic inflammatory diseases (cid+AA), autoinflammatory syndromes (auto+AA) or AA of unknown origin or idiopathic AA (idio+AA). The major organ manifestation is renal AA that can progress to end-stage renal disease (ESRD) and multiple organ failure. This study is a monocentric retrospective analysis of the renal outcome and survival of patients with cid+AA (n=34), auto+AA (n=24) and idio+AA (n=25) who were treated with cytokine-inhibiting biological disease-modifying antirheumatic drugs (bDMARDs). 83 patients with renal AA were identified and followed for a mean observational period of 4.82 years. C reactive protein (CRP), serum amyloid alpha and proteinuria were significantly reduced with bDMARD therapy. Progression to ESRD was prevented in 60% (cid+AA), 88% (auto+AA) and 81% (idio+AA) of patients. Tocilizumab was given to 34 patients with cid+AA and idio+AA and was more effective in reducing CRP and progression to ESRD and death compared with other bDMARDs. bDMARDs reduce systemic inflammation in various diseases, leading to a reduction of proteinuria and prevention of ESRD. Importantly, tocilizumab was more effective than other bDMARDs in controlling systemic inflammation in patients with chronic inflammatory diseases and idiopathic AA, leading to better renal and overall survival.

Acute kidney injury in Hodgkin’s lymphoma, non-Hodgkin lymphoma/leukemia, and lymphoplasmacytic lymphoma: One center experience

Background: Acute kidney injury (AKI) is a common complication in patients with leukemia and lymphoma. In this single-center non-interventional retrospective study from 2010 to 2022, we aimed to evaluate causes, clinical features, and pathology finding in patients with Hodgkin lymphoma (HL), non-Hodgkin lymphoma/leukemia (NHL/CLL), or lymphoplasmacytic lymphoma (LPL) and AKI. Methods: We identified 101 patients with HL, NHL/CLL, and LPL. We analyzed AKI incidence and various clinical, laboratory, and pathology parameters and outcomes. Results: About 46.5% of patients with HL, NHL/CLL, and LPL presented with AKI. The incidence of AKI was the highest in the CLL setting (65.0%), it was lower and almost equal (48.0% and 47.0%) in NHL and HL, respectively, and the lowest (14.2%) in LPL. Study group comprised of 47 patients, M/F 31/16, median age was 64.0 [52.0; 71.0] years, and the patients with HL were significantly younger ( p = 0.022). The median disease duration prior to the AKI presentation was 14 [5; 44] months. Pre-renal AKI was diagnosed in 48.9% of cases: tumor lysis syndrome (TLS), specific lymphoid infiltration (LI), and post-renal AKI presented in 12.7% each. Kidney biopsy in 49% of patients revealed LI in 39.1% of cases. Focal segmental glomerulosclerosis presented in 21.7% of cases, proliferative glomerulonephritis with monoclonal immunoglobulin deposits in 13.0%, AA amyloidosis, IgA nephropathy, and AA amyloidosis in 8.6% each. AKI recovered in 63.8% of patients and 59.5% of patients were alive and dialysis-free at last evaluation: 100% with HL versus 58.3%, 46.1%, and 0% with NHL, LL, and LPL, respectively ( p = 0.025); and 8.5% remained alive on dialysis. About 25.5% of patients died after discontinuation or without need for dialysis; and 6.3% died on dialysis. Conclusion: AKI in patients with leukemia and lymphoma is heterogeneous and most commonly caused by volume depletion. AKI recovery, though not complete, occurred in 63.8% of cases with 68% survival.

Preclinical evaluation of Tc-99m p5+14 peptide for SPECT detection of cardiac amyloidosis.

Amyloid deposition is a cause of restrictive cardiomyopathy. Patients who present with cardiac disease can be evaluated for transthyretin (TTR)-associated cardiac amyloidosis using nuclear imaging with 99mTc-labeled pyrophosphate (PYP); however, light chain-associated (AL) cardiac amyloid is generally not detected using this tracer. As an alternative, the amyloid-binding peptide p5+14 radiolabeled with iodine-124 has been shown to be an effective pan-amyloid radiotracer for PET/CT imaging. Here, a 99mTc-labeled form of p5+14 peptide has been prepared to facilitate SPECT/CT imaging of cardiac amyloidosis. A synthesis method suitable for clinical applications has been used to prepare 99mTc-labeled p5+14 and tested for peptide purity, product bioactivity, radiochemical purity and stability. The product was compared with99mTc-PYP for cardiac SPECT/CT imaging in a mouse model of AA amyloidosis and for reactivity with human tissue sections from AL and TTR patients. The 99mTc p5+14 tracer was produced with >95% yields in radiopurity and bioactivity with no purification steps required and retained over 95% peptide purity and >90% bioactivity for >3 h. In mice, the tracer detected hepatosplenic AA amyloid as well as heart deposits with uptake ~5 fold higher than 99mTc-PYP. 99mTc p5+14 effectively bound human amyloid deposits in the liver, kidney and both AL- and ATTR cardiac amyloid in tissue sections in which 99mTc-PYP binding was not detectable. 99mTc-p5+14 was prepared in minutes in >20 mCi doses with good performance in preclinical studies making it suitable for clinical SPECT/CT imaging of cardiac amyloidosis.

Coronavirus Disease 2019 Outcomes in Amyloid A Protein Amyloidosis Secondary to Rheumatic Conditions and Signs of Post- Coronavirus Disease 2019 Proteinuria Progression.

We aimed to investigate coronavirus diease 2019 (COVID-19) outcomes in patients with amyloid A protein (AA) amyloidosis secondary to rheumatic diseases and discuss factors associated with disease course. A retrospective cohort was formed from adult patients with a diagnosis of AA amyloidosis. In patients with a positive severe acute respiratory syndrome coronavirus 2 polymerase chain reaction (PCR) test, rates of hospitalization, intensive care unit admission and mortality due to COVID-19 were collected from medical records. Data regarding to demographics, comorbidities, laboratory tests, medical treatments, adherence to previous treatments during COVID-19 and treatment administered for COVID-19 were collected from hospital databases and patient reviews. In 96 patients with AA amyloidosis, 16 had COVID-19 with a positive PCR. Ten (62.5%) patients were hospitalized, 2 (12.5%) were admitted to ICU, 1 (6.25%) was died. Hospitalized patients tended to be older. Comorbidities seemed to be more frequent in hospitalized patients. None of the patients had rapid progression to end-stage renal disease post-COVID-19. Seven patients had pre-COVID-19 and post-COVID-19 proteinuria levels. Three had notable increase in proteinuria after COVID-19 in 2 of which amyloidosis treatment was revised accordingly. Despite high rates of hospitalization in AA amyloidosis patients, mortality was observed only in 1 patient. Progression of proteinuria requiring treatment adjustment may be an issue in these patients. Cite this article as: Güven SC, Erden A, Küçük H, et al. Coronavirus disease 2019 outcomes in amyloid A protein amyloidosis secondary to rheumatic conditions and signs of post-coronavirus disease 2019 proteinuria progression. Eur J Rheumatol. Published online April 4, 2024. DOI:10.5152/eurjrheum.2024.23050.

AA Amyloidosis: A Contemporary View.

Amyloid A (AA) amyloidosis is an organ- or life-threatening complication of chronic inflammatory disorders. Here, we review the epidemiology, causes, pathogenesis, clinical features, and diagnostic and therapeutic strategies of AA amyloidosis. The incidence of AA amyloidosis has declined due to better treatment of the underlying diseases. Histopathological examination is the gold standard of diagnosis, but magnetic resonance imaging can be used to detect cardiac involvement. There is yet no treatment option for the clearance of amyloid fibril deposits; therefore, the management strategy primarily aims to reduce serum amyloid A protein. Anti-inflammatory biologic agents have drastically expanded our therapeutic armamentarium. Kidney transplantation is preferred in patients with kidney failure, and the recurrence of amyloidosis in the allograft has become rare as transplant recipients have started to benefit from the new agents. The management of AA amyloidosis has been considerably changed over the recent years due to the novel therapeutic options aiming to control inflammatory activity. New agents capable of clearing amyloid deposits from the tissues are still needed.

A rare clinical case of systemic AA amyloidosis with cardiac involvement complicating ankylosing spondylitis: a case report

BackgroundAnkylosing spondylitis (AS) is a type of chronic inflammation that is most prevalent in young adults and is characterized by an inflammatory enthesiopathy that gradually develops toward ossification and ankylosis. If inflammation is left unchecked, it can potentially lead to complications such as secondary amyloidosis, also known as AA amyloidosis, involving the deposition of amyloid serum A protein. Our case presents with a thyroid localization of AA amyloidosis which is secondary to this AS. Such a case has been described in only four cases in the literature. Cardiac localization of AA amyloidosis has been exceptionally described in the literature.Case presentationWe report the case of a young patient with severe AS complicated by secondary amyloidosis with thyroid, cardiac, and probably renal localization. He was treated with anti-TNF therapy, and his condition improved significantly.ConclusionsOur case presents several localizations of AA amyloidosis secondary to this AS. Although cardiac involvement is rare in secondary AA amyloidosis, it should always be screened for, even in a cardiacly asymptomatic patient.

A case of AA amyloidosis complicated by proliferating pilomatricoma and a review of the literature.

Although AA amyloidosis is primarily caused by inflammatory conditions, associations between AA amyloidosis and solid cancers have occasionally been described. Herein, we report the case of a 48-year-old man in whom resection of a proliferating pilomatricoma with deposition of AA amyloid resulted in remission of concomitant AA gastrointestinal amyloidosis. A rapidly growing, giant, reddish, ulcerated tumor measuring 16 × 13 cm in size was identified on the upper left arm on a visit to our hospital. Gastrointestinal AA amyloidosis was diagnosed from colorectal mucosal biopsy at the same time, and weight loss and profuse diarrhea were clinically evident. As treatment, the tumor was resected with a 10-mm surgical margin. Histologically, the tumor predominantly comprised a lobular proliferation of basophilic cells peripherally, filled with eosinophilic, cornified material and shadow cells with mitoses observed in basophilic cells. Specimens revealed eosinophilic, homogeneous deposits around tumor nests, which were confirmed as amyloid deposits by positive staining with Congo red stain. These deposits were immunohistochemically positive on staining with anti-serum amyloid A antibody. Collectively, proliferating pilomatricoma with AA amyloidosis was diagnosed. After tumor resection, chronic diarrhea resolved and no amyloid deposition was apparent in colorectal biopsy. It is important to remember that if amyloid deposition is present in a tumor, aggressive tumor excision may alleviate systemic amyloidosis.

Development and Validation of Staging Systems for AA Amyloidosis.

The kidney is involved in almost 100% of cases of AA amyloidosis, a rare disease caused by persistent inflammation with long overall survival but frequent progression to end-stage kidney failure . Identification of patients with advanced disease at diagnosis is difficult, given the absence of validated staging systems. Newly diagnosed patients with AA amyloidosis from the Pavia (n=233, testing cohort) and Heidelberg (n=243, validation cohort) centers were included in the study. Cut-offs of continuous variables were determined by ROC analysis predicting death or dialysis at 24 months. Prognostic factors included in staging systems were identified by multivariable models in the testing cohort. Age ≥65 years, estimated glomerular filtration rate (eGFR) <45 mL/min/1.73m2 and elevated natriuretic peptides (type-B natriuretic peptide [BNP] >130 ng/L and/or N-terminal BNP [NT-proBNP] >1000 ng/L) were predictors of overall survival and included in the staging system (all with simplified coefficients 1). Mean 36-months overall survival was lower with higher staging system scores (score 0-1: 92%; score 2: 72%; score 3: 32%). These results were confirmed in the validation cohort. For kidney failure, variables selected to enter in the staging system model were proteinuria >3 g/24h and eGFR <35 mL/min/1.73m2 (both with simplified coefficients 1). The 36-month cumulative incidence of kidney failure was higher with higher staging system scores (score 0: 0%; score 1: 24%; score 2: 51%). Again, similar results were obtained in validation cohort. We identified and validated biomarker-based staging systems for overall survival and kidney failure in AA amyloidosis.

Predicting genetic risk factors for AA amyloidosis in Algerian patients with familial Mediterranean fever.

Renal amyloid-associated (AA) amyloidosis is a harmful complication of familial Mediterranean fever (FMF). Its occurrence involves polymorphisms and mutations in the Serum Amyloid A1 (SAA1) and Mediterranean Fever (MEFV) genes, respectively. In Algeria, the association between SAA1 variants and FMF-related amyloidosis was not investigated, hence the aim of this case-control study. It included 60 healthy controls and 60 unrelated FMF patients (39 with amyloidosis, and 21 without amyloidosis). All were genotyped for the SAA1 alleles (SAA1.1, SAA1.5, and SAA1.3), and a subset of them for the - 13C/T polymorphism by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Comparisons between genotype and allele frequencies were performed using Chi-square and Fisher tests. The SAA1.1/1.1 genotype was predominant in amyloid FMF patients, compared to non-amyloid FMF patients (p = 0.001) and controls (p < 0.0001). SAA1.1/1.5 was higher in non-amyloid patients (p = 0.0069) and in controls (p = 0.0082) than in patients with amyloidosis. Bivariate logistic regression revealed an increased risk of AA amyloidosis with three genotypes, SAA1.1/1.1 [odds ratio 7.589 (OR); 95% confidence interval (CI): 2.130-27.041] (p = 0.0018), SAA1.1/1.3 [OR 5.700; 95% CI: 1.435-22.644] (p = 0.0134), and M694I/M694I [OR 4.6; 95% CI: 1.400-15.117] (p = 0.0119). The SAA1.1/1.5 genotype [OR 0.152; 95% CI: 0.040-0.587] (p = 0.0062) was protective against amyloidosis. In all groups, the - 13C/C genotype predominated, and was not related to renal complication [OR 0.88; 95% CI: 0.07-10.43] (p = 0.915). In conclusion, in contrast to the - 13C/T polymorphism, the SAA1.1/1.1, SAA1.1/1.3 and M694I/M694I genotypes may increase the risk of developing renal AA amyloidosis in the Algerian population.

Cardiac Amyloidosis: A Contemporary Review of Medical and Surgical Therapy.

Amyloidosis is a systemic disease initiated by deposition of misfolded proteins in the extracellular space, due to which multiple organs may be affected concomitantly. Cardiac amyloidosis, however, remains a major cause of morbidity and mortality in this population due to infiltrative /restrictive cardiomyopathy. This review attempts to focus on contemporary medical and surgical therapies for the different types of cardiac amyloidosis. Amyloidosis affecting the heart are predominantly of the transthyretin type (acquired in the older or genetic in the younger patients), and the monoclonal immunoglobulin light chain (AL) type which is solely acquired. A rare form of secondary amyloidosis AA type can also affect the heart due to excessive production and accumulation of the acute-phase protein called Serum Amyloid A" (SAA) in the setting of chronic inflammation, cancers or autoinflammatory disease. More commonly AA amyloidosis is seen in the liver and kidney. Other rare types are Apo A1 and Isolated Atrial Amyloidosis (AANF). Medical therapies have made important strides in the clinical management of the two common types of cardiac amyloidosis. Surgical therapies such as mechanical circulatory support and cardiac transplantation should be considered in appropriate patients. Future research using AI driven algorithms for early diagnosis and treatment as well as development of newer genetic engineering technologies will drive improvements in diagnosis, treatment and patient outcomes.

Amyloid deposition and small vessel disease are associated with cognitive function in older adults with type 2 diabetes.

Diabetes is associated with cognitive decline, but the underlying mechanisms are complex and their relationship with Alzheimer's Disease biomarkers is not fully understood. We assessed the association of small vessel disease (SVD) and amyloid burden with cognitive functioning in 47 non-demented older adults with type-2 diabetes from the Israel Diabetes and Cognitive Decline Study (mean age 78Y, 64% females). FLAIR-MRI, Vizamyl amyloid-PET, and T1W-MRI quantified white matter hyperintensities as a measure of SVD, amyloid burden, and gray matter (GM) volume, respectively. Mean hemoglobin A1c levels and duration of type-2 diabetes were used as measures of diabetic control. Cholesterol level and blood pressure were used as measures of cardiovascular risk. A broad neuropsychological battery assessed cognition. Linear regression models revealed that both higher SVD and amyloid burden were associated with lower cognitive functioning. Additional adjustments for type-2 diabetes-related characteristics, GM volume, and cardiovascular risk did not alter the results. The association of amyloid with cognition remained unchanged after further adjustment for SVD, and the association of SVD with cognition remained unchanged after further adjustment for amyloid burden. Our findings suggest that SVD and amyloid pathology may independently contribute to lower cognitive functioning in non-demented older adults with type-2 diabetes, supporting a multimodal approach for diagnosing, preventing, and treating cognitive decline in this population.

Abstract TP29: Neurodegenerative Plasma Biomarker Associations With Cognitive Resilience in Adults With High White Matter Hyperintensity Volume: A Post-Hoc Analysis of Systolic Blood Pressure Intervention Trial Memory &amp; Cognition in Decreased Hypertension (SPRINT MIND)

Introduction: Although high cerebral white matter hyperintensity volume (WMHv) is associated with cognitive decline, many adults with high WMHv show no cognitive deficits. Neurodegenerative plasma biomarkers may be associated with cognitive decline via vascular processes causing higher WMHv such as cerebral amyloid angiopathy &amp; inflammatory small vessel disease. We determined associations of plasma amyloid β 42 (AB42), amyloid β 40 (AB40), AB42/AB40, total tau, &amp; neurofilament light chain (NfL) with cognitive resilience (CR) in adults with high WMHv using baseline MRIs &amp; measurements from SPRINT MIND. Methods: This study included baseline data from 186 SPRINT MIND participants who were in the highest WMHv tertile &amp; had available plasma biomarker concentrations &amp; Montreal Cognitive Assessment (MoCA) scores. We defined CR two ways: A) MoCA score &gt;25 or B) MoCA score &gt;22. We determined univariate &amp; adjusted odds ratios (OR) &amp; 90% confidence intervals (CI) for each aforementioned plasma biomarker with CR. Confounders in adjusted models were: age, sex, race-ethnicity (Non-Hispanic white, Non-Hispanic Black, Hispanic, or other) education (no college education, college education, or post-graduate education), smoking history (never smoker, prior smoker, or current smoker) physical activity (0, 1-4, or ≥ 5 days of vigorous physical activity), diabetes, having insurance, &amp; average systolic blood pressure. Residual confounding and effect modification by WMHv were tested in sensitivity analyses. Results: In our sample, the mean age was 72.6 years, 45.7% were female &amp; 66% were Non-Hispanic white. The median WMHv was 10.0 cm 3 (25%-75% range: 6.3 - 16.9 cm 3 ). . CR defined as MoCA scores &gt; 25 &amp; &gt;22 was present in 28.5% &amp; 56.5% of participants respectively. Lower plasma AB40 was marginally associated with CR using a MoCa cutoff of &gt;25 (OR 1.003, 90% CI: 1.001-1.006) in univariate analyses. There were no other significant (P&gt;0.1) univariate or adjusted associations between plasma biomarkers with CR using either MoCa cutoff, nor significant confounding or effect modification by WMHv (P&gt; 0.1). Conclusion: There were no significant adjusted associations between any plasma biomarker with CR. Future work should identify factors associated with CR in adults with high WMHv.

De novo AA amyloidosis in a transplant kidney

De novo AA amyloidosis in a transplant kidney

Amyloidosis and the heart

Amyloidosis is a group of infiltrative diseases based on abnormal fibrillogenesis, i.e. the ability of some proteins - amyloid precursors, under certain conditions, to form insoluble thread-like structures - fibrils. Modern classifications of amyloidosis are based on the principle of specificity of the main fibrillogen protein - the amyloid precursor. Systemic forms of amyloidosis mainly include diseases involving blood plasma proteins. Certain types of amyloidosis tend to affect certain target organs. The prognosis of the disease largely depends on which organ is most severely affected. In systemic senile amyloidosis, the cardiovascular system is predominantly affected. Serum amyloid A (AA type) is an acute-phase protein synthesized in the liver. The cardiovascular system is affected relatively rarely in systemic AA amyloidosis, in approximately 0.1-10% of cases.

A reactive systemic amyloidosis with fibrosis in a Vigova duck : A case report

A reactive systemic amyloidosis with fibrosis in a Vigova duck : A case report

A comparative urinary proteomic and metabolomic analysis between renal aa amyloidosis and membranous nephropathy with clinicopathologic correlations

Urinary omics has become a powerful tool for elucidating pathophysiology of glomerular diseases. However, no urinary omics analysis has been performed yet on renal AA amyloidosis. Here, we performed a comparative urine proteomic and metabolomic analysis between recently diagnosed renal AA amyloidosis (AA) and membranous nephropathy (MN) patients. Urine samples of 22 (8 AA, 8 MN and 6 healthy control) patients were analyzed with nLC-MS/MS and GC/MS for proteomic and metabolomic studies, respectively. Pathological specimens were scored for glomerulosclerosis and tubulointerstitial fibrosis grades. Functional enrichment analysis between AA and control groups showed enrichment in cell adhesion related sub-domains. Uromodulin (UMOD) was lower, whereas ribonuclease 1 (RNase1) and α-1-microglobulin/bikunin precursor (AMBP) were higher in AA compared to MN group. Correlations were demonstrated between UMOD-proteinuria (r = −0.48, p = 0.03) and AMBP-eGFR (r = −0.69, p = 0.003) variables. Metabolomic analysis showed myo-inositol and urate were higher in AA compared to MN group. A positive correlation was detected between RNase1 and urate independent of eGFR values (r = 0.63, p = 0.01). Enrichment in cell adhesion related domains suggested a possible increased urinary shear stress due to amyloid fibrils. UMOD, AMBP and myo-inositol were related with tubulointerstitial damage, whereas RNase1 and urate were believed to be related with systemic inflammation in AA amyloidosis. SignificanceUrinary omics studies have become a standard tool for biomarker studies. However, no urinary omics analysis has been performed yet on renal AA amyloidosis. Here, we performed a comparative urinary omics analysis between recently diagnosed renal AA amyloidosis (AA), membranous nephropathy (MN) patients and healthy controls. Pathological specimens were scored with glomerulosclerosis (G) and tubulointerstitial fibrosis (IF) grades to consolidate the results of the omics studies and correlation analyzes. Functional enrichment analysis showed enrichment in cell adhesion related sub-domains due to downregulation of cadherins; which could be related with increased urinary shear stress due to amyloid deposition and disruption of tissue micro-architecture. In comparative proteomic analyzes UMOD was lower, whereas RNase1 and AMBP were higher in AA compared to MN group. Whereas in metabolomic analyzes; myo-inositol, urate and maltose were higher in AA compared to MN group. Correlations were demonstrated between UMOD-proteinuria (r = −0.48, p = 0.03), AMBP-eGFR (r = −0.69, p = 0.003) and between RNase1-Urate independent of eGFR values (r = 0.63, p = 0.01). This study is the first comprehensive urinary omics analysis focusing on renal AA Amyloidosis to the best of our knowledge. Based on physiologic roles and clinicopathologic correlations of the molecules; UMOD, AMBP and myo-inositol were related with tubulointerstitial damage, whereas RNase1 and urate were believed to be increased with systemic inflammation and endothelial damage in AA amyloidosis.

Symptomatic SARS-CoV2 infection associated with high mortality in AA amyloidosis

Symptomatic SARS-CoV2 infection associated with high mortality in AA amyloidosis

Biological and methodological factors underlying a continuous amyloid CSF/PET imbalance model and its association with longitudinal cognition

AbstractBackgroundDiscordance between cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers of amyloid‐ß (Aß) occurs in up to 20% of individuals. Generally, Aß discordance is defined using binary cut‐offs. Given the methodological limitations of this approach, we propose a continuous Aß CSF/PET imbalance model. We investigated biological and methodological factors underlying discrepancy in these amyloid biomarkers and associations with longitudinal cognition.MethodWe included 383 non‐demented subjects (Nunimpaired = 326, Nmildly‐impaired = 57) from the AMYPAD‐PNHS cohort. Z‐scored CSF Aß42 and amyloid‐PET (Centiloids [CL]) units were fitted to a hyperbolic regression model by minimizing the Euclidian distance of the observed datapoints to the fitted line. Subject‐specific standardized residuals were derived as a measure of continuous imbalance (Zimbalance), with Zimbalance&lt;0 reflecting greater Aß abnormality in CSF relative to PET and Zimbalance&gt;0 greater Aß abnormality in PET relative to CSF (Figure‐1). Linear models adjusted for relevant covariates (Figure‐2) were run between Zimbalance and (1) methodological factors (CSF‐PET interval, CSF kit, PET tracer, and PET injected dose); (2) demographics (age, sex, education, APOE genotype) and CSF p‐tau biomarker; (3) vascular burden (white matter hyperintensities measured as Fazekas scores). Linear mixed models were used to investigate the predictive value of Zimbalance on longitudinal cognition in several domains.ResultSample characteristics are shown in Table‐1. Methodological factors were not significantly associated with Zimbalance. Increased CSF p‐tau levels were significantly associated with a higher Zimbalance (i.e. greater Aß abnormality in PET relative to CSF) (ß = 0.06±0.03, p = .033) (Figure‐2). In addition, a lower Zimbalance (i.e. greater Aß abnormality in CSF relative to PET) was associated with a higher Fazekas score (n = 189, ß = ‐0.55±0.26, p = .038) and predictive of faster cognitive decline on a language categorical fluency test (ß = ‐0.03±0.02, p = .038) (Figure‐2).ConclusionWe found that methodological factors did not contribute to a continuous model of Aß CSF/PET imbalance, suggesting that this imbalance reflects distinct biological profiles. Indeed, continuous CSF/PET imbalance showed differential associations, with greater pathological levels of aggregated Aß relative to soluble Aß being related to increased CSF p‐tau levels and excess pathological levels of soluble Aß relative to aggregated Aß to increased white matter hyperintensities and steeper cognitive decline.

Biological and methodological factors underlying a continuous amyloid CSF/PET imbalance model and its association with longitudinal cognition

AbstractBackgroundDiscordance between cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers of amyloid‐β (Aβ) occurs in up to 20% of individuals. Generally, Aβ discordance is defined using binary cut‐offs. Given the methodological limitations of this approach, we propose a continuous Aβ CSF/PET imbalance model. We investigated biological and methodological factors underlying discrepancy in these amyloid biomarkers and associations with longitudinal cognition.MethodWe included 383 non‐demented subjects (N unimpaired = 326, N mildly‐impaired = 57) from the AMYPAD‐PNHS cohort. Z‐scored CSF Aβ42 and amyloid‐PET (Centiloids [CL]) units were fitted to a hyperbolic regression model by minimizing the Euclidian distance of the observed datapoints to the fitted line. Subject‐specific standardized residuals were derived as a measure of continuous imbalance (Zimbalance), with Zimbalance&lt;0 reflecting greater Aβ abnormality in CSF relative to PET and Zimbalance&gt;0 greater Aβ abnormality in PET relative to CSF (Figure‐1). Linear models adjusted for relevant covariates (Figure‐2) were run between Zimbalance and (1) methodological factors (CSF‐PET interval, CSF kit, PET tracer, and PET injected dose); (2) demographics (age, sex, education, APOE genotype) and CSF p‐tau biomarker; (3) vascular burden (white matter hyperintensities measured as Fazekas scores). Linear mixed models were used to investigate the predictive value of Zimbalance on longitudinal cognition in several domains.ResultSample characteristics are shown in Table‐1. Methodological factors were not significantly associated with Zimbalance. Increased CSF p‐tau levels were significantly associated with a higher Zimbalance (i.e. greater Aβ abnormality in PET relative to CSF) (β = 0.06±0.03, p = .033) (Figure‐2). In addition, a lower Zimbalance (i.e. greater Aβ abnormality in CSF relative to PET) was associated with a higher Fazekas score (n = 189, β = ‐0.55±0.26, p = .038) and predictive of faster cognitive decline on a language categorical fluency test (β = ‐0.03±0.02, p = .038) (Figure‐2).ConclusionWe found that methodological factors did not contribute to a continuous model of Aβ CSF/PET imbalance, suggesting that this imbalance reflects distinct biological profiles. Indeed, continuous CSF/PET imbalance showed differential associations, with greater pathological levels of aggregated Aβ relative to soluble Aβ being related to increased CSF p‐tau levels and excess pathological levels of soluble Aβ relative to aggregated Aβ to increased white matter hyperintensities and steeper cognitive decline.