RESUMO
OBJECTIVE: To determine whether plasma phosphorylated-Tau181 (pTau181) could be used as a diagnostic biomarker of concurrent Alzheimer's disease neuropathologic change (ADNC) or amyloidosis alone, as well as a prognostic, monitoring, and susceptibility/risk biomarker for clinical outcomes in Lewy body disease (LBD). METHODS: We studied 565 participants: 94 LBD with normal cognition, 83 LBD with abnormal cognition, 114 with Alzheimer's disease, and 274 cognitively normal. Plasma pTau181 levels were measured with the Lumipulse G platform. Diagnostic accuracy for concurrent ADNC and amyloidosis was assessed with Receiver Operating Characteristic curves in a subset of participants with CSF pTau181/Aß42, and CSF Aß42/Aß40 or amyloid-ß PET, respectively. Linear mixed effects models were used to examine the associations between baseline and longitudinal plasma pTau181 levels and clinical outcomes. RESULTS: Plasma pTau181 predicted concurrent ADNC and amyloidosis in LBD with abnormal cognition with 87% and 72% accuracy, respectively. In LBD patients with abnormal cognition, higher baseline plasma pTau181 was associated with worse baseline MoCA and CDR-SB, as well as accelerated decline in CDR-SB. Additionally, in this group, rapid increases in plasma pTau181 over 3 years predicted a faster decline in CDR-SB and memory. In LBD patients with normal cognition, there was no association between baseline or longitudinal plasma pTau181 levels and clinical outcomes; however, elevated pTau181 at baseline increased the risk of conversion to cognitive impairment. INTERPRETATION: Our findings suggest that plasma pTau181 is a promising biomarker for concurrent ADNC and amyloidosis in LBD. Furthermore, plasma pTau181 holds potential as a prognostic, monitoring, and susceptibility/risk biomarker, predicting disease progression in LBD. ANN NEUROL 2024;96:526-538.
Assuntos
Doença de Alzheimer , Biomarcadores , Doença por Corpos de Lewy , Proteínas tau , Humanos , Feminino , Masculino , Idoso , Proteínas tau/sangue , Proteínas tau/líquido cefalorraquidiano , Doença por Corpos de Lewy/sangue , Doença por Corpos de Lewy/patologia , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Fosforilação , Doença de Alzheimer/sangue , Doença de Alzheimer/patologia , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/sangue , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Pessoa de Meia-Idade , Disfunção Cognitiva/sangue , Amiloidose/sangue , PrognósticoRESUMO
BACKGROUND: Dialysis-related amyloidosis (DRA) is a severe complication in end-stage kidney disease (ESKD) patients undergoing long-term dialysis treatment, characterized by the deposition of ß2-microglobulin-related amyloids (Aß2M amyloid). To inhibit DRA progression, hexadecyl-immobilized cellulose bead (HICB) columns are employed to adsorb circulating ß2-microglobulin (ß2M). However, it is possible that the HICB also adsorbs other molecules involved in amyloidogenesis. METHODS: We enrolled 14 ESKD patients using HICB columns for DRA treatment; proteins were extracted from HICBs following treatment and identified using liquid chromatography-linked mass spectrometry. We measured the removal rate of these proteins and examined the effect of those molecules on Aß2M amyloid fibril formation in vitro. RESULTS: We identified 200 proteins adsorbed by HICBs. Of these, 21 were also detected in the amyloid deposits in the carpal tunnels of patients with DRA. After passing through the HICB column and hemodialyzer, the serum levels of proteins such as ß2M, lysozyme, angiogenin, complement factor D and matrix Gla protein were reduced. These proteins acted in the Aß2M amyloid fibril formation. CONCLUSIONS: HICBs adsorbed diverse proteins in ESKD patients with DRA, including those detected in amyloid lesions. Direct hemoperfusion utilizing HICBs may play a role in acting Aß2M amyloidogenesis by reducing the amyloid-related proteins.
Assuntos
Amiloidose , Celulose , Falência Renal Crônica , Proteômica , Diálise Renal , Microglobulina beta-2 , Humanos , Amiloidose/metabolismo , Amiloidose/sangue , Amiloidose/terapia , Diálise Renal/efeitos adversos , Masculino , Feminino , Microglobulina beta-2/metabolismo , Microglobulina beta-2/sangue , Proteômica/métodos , Idoso , Celulose/química , Pessoa de Meia-Idade , Adsorção , Falência Renal Crônica/terapia , Falência Renal Crônica/metabolismo , Falência Renal Crônica/sangue , Espectrometria de Massas/métodos , Amiloide/metabolismo , Cromatografia LíquidaRESUMO
Haemostatic abnormalities and deregulated coagulation are common complications in AL amyloidosis. The relevant risks of thromboembolic and haemorrhagic events have not been thoroughly evaluated. To describe clinically significant thrombotic/haemorrhagic events in 450 consecutive patients with AL amyloidosis. Venous thromboembolic events (VTEs) were reported in 6% and arterial embolic events (AEEs) in 5% of patients, respectively, during a 55-month median follow-up. Lower albumin, lower eGFR, higher BM infiltration, soft tissue involvement, IMiD-based therapy and prior thrombosis were associated with VTE risk. Prior thrombosis was the only independent prognostic variable (HR 9.3, p = 0.001). Coronary arterial disease, prior AEE, 24-h proteinuria and higher platelet counts were associated with AEE risk. Significant bleeding events were reported in 9%, and associated mortality was 19%. Liver involvement, higher serum creatinine and higher baseline VWF:Ag levels were linked to bleeding risk. Using competing risk analysis, the cumulative probability of thrombosis/bleeding was higher during the first year following diagnosis, but a stable lower risk for both events remained for the duration of follow-up. In AL amyloidosis patients, the risk of thrombotic/arterial embolic events is significant, but the bleeding risk is also high. A multiparametric assessment is required to initiate anti-thrombotic or anti-platelet therapy appropriately.
Assuntos
Hemorragia , Amiloidose de Cadeia Leve de Imunoglobulina , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Hemorragia/etiologia , Idoso , Amiloidose de Cadeia Leve de Imunoglobulina/complicações , Amiloidose de Cadeia Leve de Imunoglobulina/mortalidade , Amiloidose de Cadeia Leve de Imunoglobulina/sangue , Trombose/etiologia , Fatores de Risco , Seguimentos , Amiloidose/complicações , Amiloidose/sangue , Amiloidose/mortalidade , Adulto , Idoso de 80 Anos ou maisRESUMO
BACKGROUND: In a Phase I study treatment with the serum amyloid P component (SAP) depleter miridesap followed by monoclonal antibody to SAP (dezamizumab) showed removal of amyloid from liver, spleen and kidney in patients with systemic amyloidosis. We report results from a Phase 2 study and concurrent immuno-positron emission tomography (PET) study assessing efficacy, pharmacodynamics, pharmacokinetics, safety and cardiac uptake (of dezamizumab) following the same intervention in patients with cardiac amyloidosis. METHODS: Both were uncontrolled open-label studies. After SAP depletion with miridesap, patients received ≤ 6 monthly doses of dezamizumab in the Phase 2 trial (n = 7), ≤ 2 doses of non-radiolabelled dezamizumab plus [89Zr]Zr-dezamizumab (total mass dose of 80 mg at session 1 and 500 mg at session 2) in the immuno-PET study (n = 2). Primary endpoints of the Phase 2 study were changed from baseline to follow-up (at 8 weeks) in left ventricular mass (LVM) by cardiac magnetic resonance imaging and safety. Primary endpoint of the immuno-PET study was [89Zr]Zr-dezamizumab cardiac uptake assessed via PET. RESULTS: Dezamizumab produced no appreciable or consistent reduction in LVM nor improvement in cardiac function in the Phase 2 study. In the immuno-PET study, measurable cardiac uptake of [89Zr]Zr-dezamizumab, although seen in both patients, was moderate to low. Uptake was notably lower in the patient with higher LVM. Treatment-associated rash with cutaneous small-vessel vasculitis was observed in both studies. Abdominal large-vessel vasculitis after initial dezamizumab dosing (300 mg) occurred in the first patient with immunoglobulin light chain amyloidosis enrolled in the Phase 2 study. Symptom resolution was nearly complete within 24 h of intravenous methylprednisolone and dezamizumab discontinuation; abdominal computed tomography imaging showed vasculitis resolution by 8 weeks. CONCLUSIONS: Unlike previous observations of visceral amyloid reduction, there was no appreciable evidence of amyloid removal in patients with cardiac amyloidosis in this Phase 2 trial, potentially related to limited cardiac uptake of dezamizumab as demonstrated in the immuno-PET study. The benefit-risk assessment for dezamizumab in cardiac amyloidosis was considered unfavourable after the incidence of large-vessel vasculitis and development for this indication was terminated. Trial registration NCT03044353 (2 February 2017) and NCT03417830 (25 January 2018).
Assuntos
Amiloidose , Anticorpos Monoclonais , Ácidos Carboxílicos , Cardiomiopatias , Tomografia por Emissão de Pósitrons , Pirrolidinas , Componente Amiloide P Sérico , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Amiloidose/sangue , Amiloidose/diagnóstico por imagem , Amiloidose/tratamento farmacológico , Amiloidose/imunologia , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/uso terapêutico , Ácidos Carboxílicos/efeitos adversos , Ácidos Carboxílicos/uso terapêutico , Cardiomiopatias/sangue , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/imunologia , Quimioterapia Combinada , Imageamento por Ressonância Magnética , Miocárdio/metabolismo , Miocárdio/patologia , Valor Preditivo dos Testes , Pirrolidinas/efeitos adversos , Pirrolidinas/uso terapêutico , Componente Amiloide P Sérico/antagonistas & inibidores , Componente Amiloide P Sérico/imunologia , Fatores de Tempo , Resultado do Tratamento , Reino Unido , Estados Unidos , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacosRESUMO
Amyloid A (AA) amyloidosis is a well-known consequence of chronic inflammatory diseases in which elevated plasma concentrations of serum amyloid A result in amyloid aggregation and organ damage. In this issue, Sikora et al. report, for the first time, an inherited form of AA amyloidosis occurring in the absence of systemic inflammation. This finding may provide novel insights into the pathogenesis of AA amyloidosis, allowing researchers to further dissect the role of inflammation from that of serum amyloid A.
Assuntos
Amiloidose , Pesquisa Biomédica , Amiloidose/sangue , Humanos , Inflamação/complicações , Proteína Amiloide A Sérica/análiseRESUMO
Introducción: la amiloidosis AA puede ser una complicación de ciertos trastornos inflamatorios crónicos, aunque entre el 21% y 50% puede ser idiopática. No existe un tratamiento específico. El tocilizumab, dirigido contra el receptor de IL-6 y orientado a disminuir la producción de SAA, podría ser eficaz. Métodos: en este estudio informamos datos de 6 pacientes con amiloidosis AA tratados con tocilizumab monoterapia subcutáneo en el período 2011-2018. Los criterios de valoración principales fueron la mejora clínica y bioquímica de los órganos afectados y los parámetros bioquímicos marcadores de inflamación. Resultados: el riñón estaba afectado en todos los pacientes, manifestándose con caída del filtrado glomerular y síndrome nefrótico. La hemorragia digestiva se presentó en un paciente y otro tenía afectación pulmonar en la biopsia. Luego del posterior al tratamiento, todos mejoraron el hematocrito, la albúmina sérica y el índice de masa corporal. El SAA disminuyó en 5 pacientes. Un paciente mejoró su función renal, mientras 4 se mantuvieron estables. Tres pacientes disminuyeron los valores de proteinuria. Conclusión: el tratamiento con tocilizumab podría ser eficaz en el tratamiento de los pacientes con amiloidosis AA. (AU)
Introduction: AA amyloidosis can be a complication of certain chronic inflammatory disorders, although between 21% and 50% can be idiopathic. There is no specific treatment. Tocilizumab, directed against the IL-6 receptor and aimed at decreasing SAA production, could be effective. Methods: in this study, we report data from 6 patients with AA amyloidosis treated with subcutaneous tocilizumab monotherapy between the period 2011-2018. The main endpoints were the clinical and biochemical improvement of the affected organs and the biochemical parameters markers of inflammation. Results: the kidney was affected in all patients, manifesting with a fall in glomerular filtration rate and nephrotic syndrome. Gastrointestinal bleeding occurred in one patient and another had lung involvement on biopsy. After treatment, all improved hematocrit, serum albumin, and body mass index. SAA decreased in 5 patients. One patient improved his kidney function, while 4 remained stable. Three patients decreased proteinuria values. Conclusion: treatment with tocilizumab could be effective in the treatment of patients with AA amyloidosis. (AU)
Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Adulto Jovem , Proteína Amiloide A Sérica/efeitos dos fármacos , Anticorpos Monoclonais Humanizados/uso terapêutico , Amiloidose/tratamento farmacológico , Índice de Massa Corporal , Receptores de Interleucina-6/efeitos dos fármacos , Anticorpos Monoclonais Humanizados/administração & dosagem , Taxa de Filtração Glomerular/efeitos dos fármacos , Hemorragia Gastrointestinal/complicações , Amiloidose/sangue , Inflamação/complicações , Pneumopatias/complicações , Síndrome Nefrótica/complicaçõesAssuntos
Amiloidose , Dexametasona/administração & dosagem , Cadeias Leves de Imunoglobulina/sangue , Lenalidomida/administração & dosagem , Mieloma Múltiplo , Ossos Pélvicos , Amiloidose/sangue , Amiloidose/diagnóstico , Amiloidose/fisiopatologia , Exame de Medula Óssea/métodos , Cardiomiopatias/diagnóstico , Cardiomiopatias/etiologia , Humanos , Imunoensaio/métodos , Fatores Imunológicos/administração & dosagem , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/fisiopatologia , Nefelometria e Turbidimetria/métodos , Paraproteinemias/diagnóstico , Ossos Pélvicos/diagnóstico por imagem , Ossos Pélvicos/patologia , Multimerização Proteica , Tomografia Computadorizada por Raios X/métodos , Resultado do TratamentoRESUMO
The severe course of COVID-19 causes systemic chronic inflammation and thrombosis in a wide variety of organs and tissues. The nature of these inflammations remains a mystery, although they are known to occur against the background of a high level of cytokine production. The high level of cytokines provokes overproduction of the Serum amyloid A (SAA) protein. Moreover, the number of studies has shown that the severe COVID-19 causes SAA overproduction. The authors of these works regard a high level of SAA exclusively as a biomarker of COVID-19. However, it should be borne in mind that overproduction of SAA can cause systemic AA amyloidosis. SAA forms cytotoxic amyloid deposits in various organs and induces inflammation and thrombosis. The consequences of COVID-19 infection are surprisingly similar to the clinical picture that is observed in AA amyloidosis. Here I present the hypothesis that AA amyloidosis is a factor causing systemic complications after coronavirus disease.
Assuntos
Amiloidose , COVID-19 , Proteína Amiloide A Sérica , Amiloidose/sangue , Amiloidose/fisiopatologia , Amiloidose/virologia , Biomarcadores , COVID-19/complicações , COVID-19/fisiopatologia , Humanos , InflamaçãoRESUMO
BACKGROUND: Serum uric acid (SUA) affects the reaction of oxidative stress and free radicals in the neurodegenerative processes. However, whether SUA impacts Alzheimer's disease (AD) pathology remains unclear. OBJECTIVE: We aimed to explore whether high SUA levels can aggravate the neurobiological changes of AD in preclinical AD. METHODS: We analyzed cognitively intact participants (n = 839, age 62.16 years) who received SUA and cerebrospinal fluid (CSF) biomarkers (amyloid-ß [Aß], total tau [t-Tau], and phosphorylated tau [p-Tau]) measurements from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) database using multivariable-adjusted linear models. RESULTS: Levels of SUA in the preclinical AD elevated compared with the healthy controls (p = 0.007) and subjects with amyloid pathology had higher concentration of SUA than controls (p = 0.017). Roughly, equivalent levels of SUA displayed among cognitively intact individuals with or without tau pathology and neurodegeneration. CSF Aß1 - 42 (p = 0.019) and Aß1 - 42/Aß1 - 40 (p = 0.027) were decreased and CSF p-Tau/Aß1 - 42 (p = 0.009) and t-Tau/Aß1 - 42 (p = 0.043) were increased with the highest (>â75th percentile) SUA when compared to lowest SUA, implying a high burden of cerebral amyloidosis in individuals with high SUA. Sensitivity analyses using the usual threshold to define hyperuricemia and precluding drug effects yielded robust associations. Nevertheless, the quadratic model did not show any U-shaped relationships between them. CONCLUSION: SUA may aggravate brain amyloid deposition in preclinical AD, which corroborated the detrimental role of SUA.
Assuntos
Doença de Alzheimer/etiologia , Amiloidose/etiologia , Cognição/fisiologia , Ácido Úrico/sangue , Idoso , Doença de Alzheimer/sangue , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Amiloidose/sangue , Biomarcadores/líquido cefalorraquidiano , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/líquido cefalorraquidiano , Fosforilação , Proteínas tau/líquido cefalorraquidianoAssuntos
Amiloidose/diagnóstico , Cardiomiopatias/diagnóstico , Amiloidose/sangue , Amiloidose/diagnóstico por imagem , Biomarcadores/sangue , Técnicas de Imagem Cardíaca , Cardiomiopatias/sangue , Cardiomiopatias/diagnóstico por imagem , Ecocardiografia , Eletrocardiografia , Humanos , Imageamento por Ressonância Magnética , Natriuréticos/sangue , Troponina/sangueRESUMO
BACKGROUND: Familial Mediterranean fever (FMF) is characterized by sporadic, recurrent attacks of fever and serosal inflammation. AA amyloidosis (AAA) is a disorder characterized by the extracellular tissue deposition of serum amyloid A protein (SAA). Azurocidin is a neutrophil-derived granule protein. We aimed to investigate the significance of azurocidin in FMF and AAA and the correlation between azurocidin levels and carotid artery intima media thickness (CA-IMT) and cardiovascular plaque existence. METHODS: A sum of 52 FMF patients were enrolled in the study. FMF patients were composed of two groups. Group-1 included 30 patients with non-complicated FMF. Group-2 included 22 patients whom received renal transplantation due to FMF complicated with AAA and being followed up at stable state for at least one year. 24 healthy individuals who matched with FMF patients in terms of age and gender consisted the control group. RESULTS: We found statistically significant difference between patient and control groups in terms of urea (38.52 ± 19.96 mg/dl vs 29.08 ± 5.83 mg/dl; p = 0.003), creatinine (1.11 ± 0.39 mg/dl vs 0.91 ± 0.16 mg/dl; p = 0.002), serum uric acid (6.2 ± 2 mg/dl vs 4.5 ± 0.9 mg/dl; p < 0.001), serum CRP (8.62 ± 9.5 mg/dl vs 3.91 ± 3.9 mg/dl; p = 0.004), ferritin (151.4 ± 317 ng/ml vs 33.3 ± 34 ng/ml; p = 0.014), white blood cell (WBC) levels (7.97 ± 2.3 × 103/µL vs 6.6 ± 1.7 × 103/µL; p = 0.018), serum azurocidin levels (137.16 ± 65.62 ng/ml vs 102.35 ± 51.61 ng/ml; p = 0.015) and mean CA-IMT (0.57 ± 0.15 mm vs 0.47 ± 0.07 mm; p = 0.001). Comparison of group 1 and group 2 revealed statistically significant differences in terms of urea (26 ± 8 mg/dl vs 54 ± 19 mg/dl; p < 0.001), creatinine (0.87 ± 0.1 mg/dl vs 1.44 ± 0.3 mg/dl; p < 0.001), estimated glomerular filtration rate (eGFR) (99 ± 21 ml/min/1.73m2 vs 53 ± 16 ml/min/1.73m2; p < .001), uric acid (4.9 ± 1.3 mg/dl vs 7.6 ± 1.7 mg/dl; p < 0.001), ferritin (31.7 ± 27 ng/ml vs 292.8 ± 431 ng/ml; p = 0.010) and albumin (4.5 ± 0.3 g/dl vs 4.1 ± 0.3 g/dl; p = 0.001). There was no statistically significant difference between group 1 and group 2 in terms of mean CA-IMT (CA-IMT (M) (mm): 0.54 ± 0.14 vs 0.62 ± 0.17, p = 0.057). Serum azurocidin levels were not significantly different between group 1 and group 2 (121.73 ± 53.24 ng/ml vs 158.19 ± 75.77 ng/ml; p = 0.061). In multivariate linear regression analysis (variables: MBP, urea, creatinine, eGFR, ferritin, uric acid, CA-IMT) azurocidin was independently associated with urea (t:2.658; p = 0.010) and CA-IMT (t:2.464; p = 0.017). DISCUSSION: Based on our findings, azurocidin seems to be a good inflammation marker in patients with FMF. Increase in azurocidin levels might be associated with development of amyloidosis. Also, serum azurocidin levels may be used as a predictor of both inflammatory state and cardiovascular risk, especially when used with other markers such as CA-IMT.
Assuntos
Amiloidose/sangue , Amiloidose/complicações , Peptídeos Catiônicos Antimicrobianos/sangue , Espessura Intima-Media Carotídea , Febre Familiar do Mediterrâneo/sangue , Febre Familiar do Mediterrâneo/complicações , Fatores de Risco de Doenças Cardíacas , Proteína Amiloide A Sérica , Adulto , Peptídeos Catiônicos Antimicrobianos/fisiologia , Proteínas Sanguíneas/fisiologia , Correlação de Dados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteína Amiloide A Sérica/análiseRESUMO
Systemic amyloidosis of the immunoglobulin light-chain (AL) or transthyretin type (ATTR) is a multisystem protein deposition disease that often involves the heart. Delays in diagnosis are very common and can have detrimental consequences on patient outcomes. Because both major types can now be distinguished quickly and treated effectively, clear approaches are required. There have been advances in radioisotope scintigraphy, monoclonal protein testing and mass spectrometry for typing that need coordinated application. We have entered an era in which rapid diagnosis and ready therapy will save lives, therefore we must develop coherent approaches to this multisystem disease. The prognosis for AL has improved significantly with the incorporation of novel agents such as proteasome inhibitors, immunomodulators and monoclonal antibodies against plasma cells. Multiple independent studies have demonstrated the efficacy of these agents in AL, though tolerability can become an issue with dose reductions required in many cases. Median overall survival for patients achieving complete responses after stem cell transplant and consolidation exceeds a decade. The prognosis for ATTR, both age-related wild-type (ATTRwt) and hereditary due to variants of transthyretin (ATTRv), has improved as well due to the availability of the stabilizer tafamidis and the RNA-interference agents patisiran and inotersen. In both AL and ATTR, with elimination or suppression of the pathologic amyloid-forming protein, symptomatic involvement of the heart, kidneys and peripheral nervous system can improve as well. In this review, we present the current state of diagnosing and treating the two major types of systemic amyloidosis, emphasizing the coherent clinical application of the new tools and treatments. Implementation of the approaches we provide will enable rapid identification of amyloid type and rational selection of therapy.
Assuntos
Amiloidose/complicações , Amiloidose/diagnóstico , Cardiomiopatias/diagnóstico , Cardiomiopatias/etiologia , Amiloidose/sangue , Amiloidose/etiologia , Biomarcadores , Tomada de Decisão Clínica , Diagnóstico Tardio , Diagnóstico Diferencial , Testes Diagnósticos de Rotina , Gerenciamento Clínico , Suscetibilidade a Doenças , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina/sangue , Amiloidose de Cadeia Leve de Imunoglobulina/complicações , Amiloidose de Cadeia Leve de Imunoglobulina/etiologia , Espectrometria de Massas , Pré-Albumina/genética , Pré-Albumina/metabolismoRESUMO
OBJECTIVE: Amyloid A nephropathy of FMF usually progresses over many years to end-stage renal disease (ESRD). We aim to describe an acute condition, termed here 'amyloid storm', typically manifesting with a rapid (≤2 weeks) increase in serum creatinine and urine protein, that has never been characterized in FMF amyloidosis. METHODS: This retrospective analysis features amyloid storm by comparing between FMF amyloidosis patients who have experienced an episode of amyloid storm (study group) and matched patients who have not (control group). The primary outcome was ESRD or death within 1 year from study entry. Featured data were retrieved from hospital files. RESULTS: The study and control groups, each comprising 20 patients, shared most baseline characteristics. However, they differed on the time from FMF onset to reaching serum creatinine of 1.2 mg/dl [26.5 years (s.d. 15.15) vs 41.55 (10.98), P = 0.001] and the time from the onset of proteinuria to study entry [8.8 years (s.d. 6.83) vs 15.75 (13.05), P = 0.04], culminating in younger age at study entry [39.95 years (s.d. 16.81) vs 48.9 (9.98), respectively, P = 0.05] and suggesting an accelerated progression of kidney disease in the study group. Within 1 year from study entry, 16 patients in the study and 3 in the control groups reached the primary endpoint (P = 0.000). The major triggers of amyloid storm were infections, occurring in 17 of 20 patients. CONCLUSION: Amyloid storm is a complication of FMF amyloidosis, induced by infection and associated with poor prognosis and death.
Assuntos
Injúria Renal Aguda/fisiopatologia , Amiloidose/fisiopatologia , Febre Familiar do Mediterrâneo/fisiopatologia , Infecções/epidemiologia , Falência Renal Crônica/epidemiologia , Proteinúria/fisiopatologia , Injúria Renal Aguda/sangue , Injúria Renal Aguda/etiologia , Adulto , Amiloidose/sangue , Amiloidose/etiologia , Estudos de Casos e Controles , Creatinina/sangue , Progressão da Doença , Febre Familiar do Mediterrâneo/complicações , Feminino , Humanos , Falência Renal Crônica/sangue , Falência Renal Crônica/etiologia , Masculino , Pessoa de Meia-Idade , Mortalidade , Prognóstico , Proteinúria/etiologia , Fatores de Risco , Proteína Amiloide A Sérica , Adulto JovemRESUMO
BACKGROUND: Timely recognition of cardiac amyloidosis is clinically important, but the diagnosis is frequently delayed. OBJECTIVES: We sought to identify a multi-modality approach with the highest diagnostic accuracy in patients evaluated by cardiac biopsy, the diagnostic gold standard. METHODS: Consecutive patients (Nâ¯=â¯242) who underwent cardiac biopsy for suspected amyloidosis within an 18-year period were retrospectively identified. Cardiac biomarker, ECG, and echocardiography results were examined for correlation with biopsy-proven disease. A prediction model for cardiac amyloidosis was derived using multivariable logistic regression. RESULTS: The overall cohort was characterized by elevated BNP (median 727â¯ng/mL), increased left ventricular wall thickness (IWT; median 1.7â¯cm), and reduced voltage-to-mass ratio (median 0.06â¯mm/[g/m2]). One hundred and thirteen patients (46%) had either light chain (nâ¯=â¯53) or transthyretin (nâ¯=â¯60) amyloidosis by cardiac biopsy. A prediction model including age, relative wall thickness, left atrial pressure by E/e', and low limb lead voltage (<0.5â¯mV) showed good discrimination for cardiac amyloidosis with an optimism-corrected c-index of 0.87 (95% CI 0.83-0.92). The diagnostic accuracy of this model (79% sensitivity, 84% specificity) surpassed that of traditional screening parameters, such as IWT in the absence of left ventricular hypertrophy on ECG (98% sensitivity, 20% specificity) and IWT with low limb lead voltage (49% sensitivity, 91% specificity). CONCLUSION: Among patients with an advanced infiltrative cardiomyopathy phenotype, traditional biomarker, ECG, and echocardiography-based screening tests have limited individual diagnostic utility for cardiac amyloidosis. A prediction algorithm including age, relative wall thickness, E/e', and low limb lead voltage improves the detection of cardiac biopsy-proven disease.
Assuntos
Neuropatias Amiloides Familiares/diagnóstico , Cardiomiopatias/diagnóstico , Amiloidose de Cadeia Leve de Imunoglobulina/diagnóstico , Fatores Etários , Idoso , Neuropatias Amiloides Familiares/sangue , Neuropatias Amiloides Familiares/patologia , Neuropatias Amiloides Familiares/fisiopatologia , Amiloidose/sangue , Amiloidose/diagnóstico , Amiloidose/patologia , Amiloidose/fisiopatologia , Biópsia , Velocidade do Fluxo Sanguíneo , Cardiomiopatias/sangue , Cardiomiopatias/patologia , Regras de Decisão Clínica , Ecocardiografia , Eletrocardiografia , Feminino , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/patologia , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina/sangue , Amiloidose de Cadeia Leve de Imunoglobulina/patologia , Amiloidose de Cadeia Leve de Imunoglobulina/fisiopatologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Peptídeo Natriurético Encefálico/sangue , Tamanho do Órgão , Fatores Sexuais , Troponina I/sangueRESUMO
Previous studies showed that injection of tissue extracts containing amyloid-ß (Aß) aggregates accelerate amyloid deposition in the brain of mouse models of Alzheimer's disease (AD) through prion-like mechanisms. In this study, we evaluated whether brain amyloidosis could be accelerated by blood infusions, procedures that have been shown to transmit prion diseases in animals and humans. Young transgenic mice infused with whole blood or plasma from old animals with extensive Aß deposition in their brains developed significantly higher levels brain amyloidosis and neuroinflammation compared to untreated animals or mice infused with wild type blood. Similarly, intra-venous injection of purified Aß aggregates accelerated amyloid pathology, supporting the concept that Aß seeds present in blood can reach the brain to promote neuropathological alterations in the brain of treated animals. However, an amyloid-enhancing effect of other factors present in the blood of donors cannot be discarded. Our results may help to understand the role of peripheral (amyloid-dependent or -independent) factors implicated in the development of AD and uncover new strategies for disease intervention.
Assuntos
Doença de Alzheimer/sangue , Peptídeos beta-Amiloides/sangue , Amiloidose/sangue , Transfusão de Sangue , Encéfalo/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Amiloidose/genética , Amiloidose/metabolismo , Amiloidose/patologia , Animais , Transfusão de Componentes Sanguíneos , Encéfalo/patologia , Humanos , Camundongos , Camundongos TransgênicosRESUMO
OBJECTIVES: Renal amyloidosis (RA) is a rare protein misfolding disorder that prompts progressive renal insufficiency. This study aimed to decipher proteomic changes in human sera to understand the pathophysiology and molecular mechanisms underlying the disease development, hence assisting in the diagnosis of RA. METHODS: Serum proteomic analysis was performed using a gel-based approach followed by MALDI-TOF MS. RA patients with age and sex matched healthy volunteers were recruited from Max Super Speciality Hospital, New Delhi, India. RESULTS: Proteome profiles of serum revealed eight differentially expressed proteins namely, Zinc finger protein 624, Protein FAM183A, Calcium-binding mitochondrial carrier protein Scamc-3, V-type proton ATPase 116 kDa subunit A isoforms 2, Protein TXNRD3NB, ATP - dependent RNA helicase, Troponin C and Mitogen-activated protein kinase kinase kinase 7. These proteins were reported first time in RA. The increased levels of MAP3K7 and TROPONIN C were validated by bio-layer interferometry and their diagnostic accuracy was evaluated by ROC curve analysis. The differentially expressed proteins were predominantly associated with vesicular trafficking, transcriptional regulation, metabolic processes, apoptotic process and mitochondrial metabolism. CONCLUSION: The results indicate that these proteomic signatures may be considered as potential molecular targets for RA diagnostics and therapeutics subject to validation on large sample size. Abbreviations: AßP= Amyloid-beta protein, Aß=Amyloid-beta, AL= Light chain amyloidosis, AA= Amyloid A, ALECT2= LECT2 amyloidosis, APS= Ammonium persulfate CKD= Chronic Kidney Diseases, EBRT= external beam radiation therapy, ESRD= End-Stage Kidney Disease, Glis2= Gli-similar 2, JNK= c-Jun NH 2-terminal kinase, MAPK= Mitogen-Activated Protein Kinase, MM=Multiple Myeloma, PHD= Prolyl hydroxylase, RA = Renal Amyloidosis, SAA= Serum Amyloid A, SD= Standard Deviation, Sepp= Selenoprotein, SCC= Squamous cell carcinoma, SDS= Sodium dodecyl sulfate, TEMED = tetramethyl ethylenediamine, TGF-Beta-1=Transforming growth factor- Beta-1, Trx = Thioredoxin, TrxR= Thioredoxin reductase.
Assuntos
Amiloidose/sangue , Nefropatias/sangue , MAP Quinase Quinase Quinases/sangue , Troponina C/sangue , Eletroforese em Gel Bidimensional , Humanos , Interferometria , Proteínas de Membrana/sangue , Mitocôndrias/metabolismo , Proteômica/métodosAssuntos
Amiloidose/complicações , Anticorpos Monoclonais Humanizados/uso terapêutico , Febre Familiar do Mediterrâneo/complicações , Nefropatias/diagnóstico , Nefropatias/tratamento farmacológico , Nefropatias/etiologia , Amiloidose/sangue , Amiloidose/diagnóstico , Amiloidose/terapia , Anticorpos Monoclonais Humanizados/administração & dosagem , Suscetibilidade a Doenças , Humanos , Terapia de Alvo Molecular , Proteína Amiloide A Sérica , Resultado do TratamentoRESUMO
Secondary amyloid A (AA) amyloidosis, which is a disorder of protein conformation and metabolism, is an important serious complication of inflammatory diseases, especially rheumatoid arthritis (RA). AA amyloidosis develops when AA fibrils, which are derived from the acute-phase reactant, serum amyloid AA (SAA) protein, in the circulation, are deposited in organs and cause systemic organ dysfunction. Caplan's syndrome, or rheumatoid pneumoconiosis, is a rare type of lung disease in which individuals suffering from RA develop lung nodules that are associated with occupational exposure to silica and coal dust. Confirmation of diagnosing as Caplan's syndrome requires the patient's occupational history, imaging studies, and serology. A 72-year-old male, working as a tunnel construction worker for 38 years, with RA who had both chronic cardiac and renal dysfunction was referred to our hospital. He received a diagnosis of pneumoconiosis about 20 years ago, after which he was also diagnosed with RA. So far we performed medical English literature searches on the combination of Caplan's syndrome with AA amyloidosis; there were no articles in relation to such association. Although RA is one of the most common underlying diseases that occur with AA amyloidosis, our report here is the first description of a case of Caplan's syndrome associated with AA amyloidosis. In this report, we provide details about this rare disease occurring with AA amyloidosis and discuss on the possible pathogenesis of AA amyloidosis from a genetic point of aetiological view.
Assuntos
Amiloidose/diagnóstico , Amiloidose/etiologia , Síndrome de Caplan/complicações , Suscetibilidade a Doenças , Proteína Amiloide A Sérica , Idoso , Amiloidose/sangue , Biomarcadores , Síndrome de Caplan/diagnóstico , Comorbidade , Predisposição Genética para Doença , Humanos , MasculinoRESUMO
PURPOSE OF REVIEW: This review addresses normal and pathologic functions of serum amyloid A (SAA), an enigmatic biomarker of inflammation and protein precursor of AA amyloidosis, a life-threatening complication of chronic inflammation. SAA is a small, highly evolutionarily conserved acute-phase protein whose plasma levels increase up to one thousand-fold in inflammation, infection, or after trauma. The advantage of this dramatic but transient increase is unclear, and the complex role of SAA in immune response is intensely investigated. This review summarizes recent advances in our understanding of the structure-function relationship of this intrinsically disordered protein, outlines its newly emerging beneficial roles in lipid transport and inflammation control, and discusses factors that critically influence its misfolding in AA amyloidosis. RECENT FINDINGS: High-resolution structures of lipid-free SAA in crystals and fibrils have been determined by x-ray crystallography and electron cryo-microscopy. Low-resolution structural studies of SAA-lipid complexes, together with biochemical, cell-based, animal model, genetic, and clinical studies, have provided surprising new insights into a wide range of SAA functions. An emerging vital role of SAA is lipid encapsulation to remove cell membrane debris from sites of injury. The structural basis for this role has been proposed. The lysosomal origin of AA amyloidosis has solidified, and its molecular and cellular mechanisms have emerged. Recent studies have revealed molecular underpinnings for understanding complex functions of this Cambrian protein in lipid transport, immune response, and amyloid formation. These findings help guide the search for much-needed targeted therapies to block the protein deposition in AA amyloidosis.