Amyloid-Journal of Protein Folding Disorders最新文献

Introduction: Transthyretin (ATTR) amyloidosis is an ultimately fatal disease. While approved therapies slow disease progression, the cost of care can be significant for patients. The objective of this survey was to describe the factors associated with financial toxicity of ATTR amyloidosis and the economic burden of care and treatment.

Methods: The Amyloidosis Research Consortium (ARC) conducted an online survey in the United States for patients with ATTR amyloidosis and their caregivers. Financial toxicity was assessed using the COmprehensive Score for Financial Toxicity (COST). Multivariate linear regression was used to identify factors associated with financial toxicity controlling for key sociodemographic and patient characteristics.

Results: Of 452 respondents, 249 (55%) reported financial toxicity. Respondents who reported financial toxicity predominantly had ATTRv amyloidosis, were younger, non-white, had a household income <$100,000, had multiple sources of insurance, and were less frequently retired. Respondents reported using several ways to offset the cost of treatment.

Conclusions: Patients with ATTR amyloidosis experience significant financial distress that is comparable to patients with cancer, and as a result, many patients delay treatment or pay for treatment using savings and/or borrowing money. African American respondents (vs white) were significantly at risk.

Background: Each monoclonal antibody light chain associated with AL amyloidosis has a unique sequence. Defining how these sequences drive amyloid deposition could facilitate faster diagnosis and lead to new treatments.

Methods: Light chain sequences are collected in the AL-Base repository. Monoclonal sequences from AL amyloidosis, multiple myeloma and the healthy polyclonal immune repertoire were compared to identify differences in precursor gene use, mutation frequency and physicochemical properties.

Results: AL-Base now contains 2,200 monoclonal light chain sequences from AL amyloidosis and other plasma cell dyscrasias. Sixteen germline precursor genes were enriched in AL amyloidosis, relative to multiple myeloma and the polyclonal repertoire. Two genes, IGKV1-16 and IGLV1-36, were infrequently observed but highly enriched in AL amyloidosis. The number of mutations varied widely between light chains. AL-associated κ light chains harboured significantly more mutations compared to multiple myeloma and polyclonal sequences, whereas AL-associated λ light chains had fewer mutations. Machine learning tools designed to predict amyloid propensity were less accurate for new sequences than their original training data.

Conclusions: Rarely-observed light chain variable genes may carry a high risk of AL amyloidosis. New approaches are needed to define sequence-associated risk factors for AL amyloidosis. AL-Base is a foundational resource for such studies.

Aims: To evaluate the predictive value of the Columbia score in patients with transthyretin amyloid cardiomyopathy (ATTR-CM).

Methods: Observational study based in a prospective, multi-centre registry of patients with ATTR-CM recruited between January-2018 and December-2023 in 7 Spanish hospitals. The Baseline Columbia score was correlated by means of multivariable Cox's regression with study endpoints all-cause death and all-cause death or heart failure (HF) hospitalisation. Discriminative capacity was evaluated by means of Harrell's C statistics and area under 2-year time-dependent receiver-operator curves.

Results: We studied 374 patients with ATTR-CM. Columbia score was independently associated with increased risk of all-cause death (adjusted HR per 1 point = 1.30, 95% CI 1.17-1.45) and all-cause death or HF hospitalisation (adjusted HR per 1 point = 1.38, 95% 1.26-1.50). The score showed moderate discriminative capacity for all-cause death (Harrell's C = 0.653) and all-cause death or HF hospitalisation (Harrell's C = 0.697). The area under the 2-year time-dependent receiver-operator curve was 0.594 for all-cause death and 0.669 for all-cause death or HF hospitalisation. Columbia's score was adequately calibrated for both outcomes.

Conclusions: We studied the prognostic performance of the Columbia score in a Spanish prospective cohort of patients with ATTR-CM. The score showed adequate calibration and moderate discriminative capacity for predicting death and HF hospitalisations.

Background: Accurate tissue typing in amyloidosis is essential to provide appropriate therapy for individual patients.

Objective: To get a real-life overview of typing strategies worldwide.

Methods: The International Society of Amyloidosis (ISA) performed an online questionnaire survey among ISA members. We prepared questionnaire sheets for referral institutions (Category 1; C1), institutions performing amyloid typing for internal requests only (C2), and institutions outsourcing amyloid typing to referral institutions (C3), respectively.

Results: Seventy-six institutions participated in this survey, including C1 (n = 33), C2 (n = 20) and C3 (n = 23) institutions. Multiple typing methods were available across the responding institutions, including immunohistochemistry (85% of C1/C2 institutions), immunofluorescence microscopy (43%), genetic analysis (77%) and mass spectrometric analysis (42%). Commercial antibodies were used worldwide for immunohistochemistry. C1 institutions in Europe and Asia also used various in-house antibodies. Ninety-three percent of institutions performed genetic analysis of TTR gene, followed by APOA1 (43%), FGA, GSN, LYZ (33%) and APOA2 (31%). Hierarchical referral flows of mass spectrometric analysis, immunohistochemistry and genetic analysis were observed regionally and internationally. Globalization and centralization of referral flows were more prominent for mass spectrometric analysis.

Conclusion: These data provide an assessment of the current state, enabling improvement in capabilities of amyloid typing worldwide and enhancing regional/international networks.

AA amyloidosis is a prototypic example of systemic amyloidosis: it results from the prolonged overproduction of SAA protein produced in response to chronic inflammation. AA amyloidosis primarily affects the kidneys, liver, spleen, gastrointestinal tract, leading to a variety of symptoms. First, this review examines AA amyloidosis in humans, focusing on pathogenesis, clinical presentation, and diagnosis and then in animals. In fact AA amyloidosis is the only systemic amyloidosis that has been largely documented in a remarkable number of vertebrate species: mammals, birds, and fishes, especially in individuals with comorbidities, chronic stress, or held in captivity. Secondly, here, we summarise independent sets of evidence obtained on different animal species, exploring the possible transmissibility of AA amyloidosis especially in crowded or confined populations. Finally, biochemical and structural data on native SAA and on AA amyloid fibrils from human, murine, and cat ex vivo samples are discussed. The available structural data depict a complex scenario, where SAA can misfold forming highly different amyloid assemblies. This review highlights the complexity of AA amyloidosis, emphasising the need for further research into its spread in the animal kingdom, its structural aspects, and pathogenetic mechanisms to evaluate its impact on human and animal health.

Background: Cardiac AL and ATTR are potentially fatal cardiomyopathies. Current therapies do not address mechanisms of tissue dysfunction because these remain unknown. Our prior work focused on the amyloid plaque proteome, which may not capture tissue-wide proteomic alterations.

Objectives: To evaluate mechanisms of tissue dysfunction in cardiac AL and ATTR using a full biopsy tissue proteomics approach.

Methods: We performed proteomics analysis on 76 ATTR and 27 AL diagnostic endomyocardial biopsies.

Results: Stage-3 AL patients exhibited increased coagulation, extracellular matrix remodelling (ECM), epithelial-to-mesenchymal transition (EMT), complement activation, hypoxia, and clathrin-mediated endocytosis pathways vs. stages-1/2, with decreased healthy cardiac metabolism. In stages-2 and 3 ATTR, immunoglobulin proteins, complement, and keratinisation pathways were increased compared to stage-1. Unsupervised analyses identified an ATTR group with worse survival characterised by upregulated complement and downregulated metabolic pathways. Compared to ATTR, AL had higher clathrin-mediated endocytosis, mRNA splicing, and ribosomal proteins, while ATTR had higher complement levels.

Conclusions: This study identifies known processes dysregulated in heart failure with preserved ejection fraction as well as novel pathways responsible for tissue damage. Our results support an immune-mediated mechanism of tissue toxicity in cardiac amyloidosis, especially among patients with worse outcomes.