Amyloid-Journal of Protein Folding Disorders最新文献

Background: The association between immunoglobulin light chain variable (IGVL) gene usage and clinicopathological features in renal AL amyloidosis requires further research. This study analyzed IGVL genes and their associations with clinicopathological characteristics, organ involvement and survival outcomes in a Chinese cohort.

Methods: We retrospectively enrolled 273 renal AL amyloidosis patients. Amyloid deposits were microdissected and subjected to mass spectrometry (MS)-based proteomics to identify IGVL genes. Clinicopathological features, organ involvement and survival data were systematically analyzed.

Results: IGVL genes were successfully identified in 250 patients (92%). IGLV6-57 (32%) was predominant, IGKV1 family (12%) was the most prevalent in AL-κ cases. IGLV6-57 was associated with a higher rate of full nephrotic syndrome, while was linked to milder vascular amyloid deposition and total amyloid deposition. IGKV1 was associated with heavier amyloid burden, severe interstitial inflammation and a higher rate of hepatic involvement, IGLV6-57 was correlated with reduced hepatic involvement. IGLV1-51 potentially predicted rapid renal progression and dialysis risk.

Conclusion: The IGVL gene usage is associated with distinct clinicopathological features in renal AL amyloidosis, IGLV6-57 is linked to a higher frequency of full nephrotic syndrome, IGKV1 is associated with severe kidney structural damage and hepatic tropism, and IGLV1-51 potentially predicts poor renal survival.

Background: transthyretin cardiac amyloidosis (ATTR-CA) is an infiltrative disease associated with several comorbidities such as Bleeding. The aim of this study was to evaluate the incidence of bleeding in patients with ATTR-CA and the underlying risk factors that promote bleeding.

Methods: retrospective observational study of a cohort of patients with ATTR-CA diagnosed from 1st April 2016 to 31st December 2023. Bleeding risk was calculated according to HAS-BLED score and bleeding events at follow-up were analysed.

Results: 184 patients were diagnosed with a median age of 84 years [IQR 79-88], 154 (84%) males. 118 patients (64%) were on anticoagulant therapy (AC). 91 patients (50%) had a bleeding event, with a total of 189 events recorded and a median time to bleeding of 23 months [IQR 10-68]. 26 patients (29%) had severe haemorrhages and 3 patients died of haemorrhagic causes. The incidence rate was 50 bleeds per 100 patient-years and 57 per 100 patient-years in AC patients. AC resulted in a 2.5-fold raise in bleeding (95% CI 1.4-4.8; p = .003) and a score ≥2 on HAS-BLED scale in a 5.4-fold increase (95%CI 2.6-11; p < .001).

Conclusion: bleeding is a frequent complication in ATTR-CA, with a higher risk in those individuals with a HAS-BLED score ≥2 and/or on AC. These findings could be considered in risk stratification and therapeutic decision-making.

Background: The amyloid-β peptide 42 (Aβ42) forms fibrillar aggregates that are a hallmark of Alzheimer's disease. While recent therapeutic strategies targeting Aβ42 fibrils and oligomers have shown promise, safer and more effective interventions are still needed. Noninvasive brain stimulation (NIBS) techniques such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) have emerged as potential complementary approaches, yet the molecular mechanisms by which electric fields influence amyloid aggregation remain poorly understood.

Methods: We performed atomistic molecular dynamics simulations to investigate the response of Aβ42 fibrils to static electric fields of increasing strength. Simulations were based on an ex vivo fibril structure with reconstructed N-terminal regions, and different structural restraint conditions were used to disentangle surface and core effects.

Results: Electric fields perturb the disordered N-terminal 'fuzzy coat', altering its conformational dynamics and weakening its interactions with the fibril core, thereby modifying the fibril surface properties. Simulations with unrestrained fibril ends further reveal increased fluctuations in core residues, indicating field-induced destabilization that may hinder elongation.

Conclusions: These findings provide molecular-level insight into how static electric fields can modulate amyloid fibril formation and propagation, offering a possible mechanistic basis for the effects of tDCS and related brain stimulation techniques.

Background: Atrial fibrillation (AF) is common and poorly tolerated in cardiac amyloidosis (CA) patients. No current tool assesses AF risk in this population.

Methods: We enrolled patients with light chain (AL) or transthyretin (ATTR) CA, with no prior history of AF at diagnosis between January 2015 and September 2023 across three university hospitals. Clinical, biochemical and electrocardiographic parameters were retrospectively collected and their predictive value for AF was assessed.

Results: A total of 169 patients were included (56.2% wild-type (wt) ATTR, 35.5% AL and 8.3% variant (v) ATTR). Over a median follow-up of 21 months, 55 patients (33%) presented a first episode of AF. Five independent predictors for AF were identified using multivariate logistic regression model: obstructive sleep apnea, hypertension, CA subtype, P wave duration ≥120 ms, 1st degree atrioventricular (AV) block. Based on these variables, the Amy-Lyon AF score (range 0-46) was developed to estimate AF risk (area under the receiver operating characteristic (ROC) curve (AUC) 0.768 [0.685-0.852], p < .001). At two years of follow-up, the incidence of AF reached 82.7% in patients with a score >28. In 80 patients, the AUC of the Amy-Lyon AF score was higher than that of left atrial strain.

Conclusions: Five simple and readily available predictors may stratify the risk of AF in CA.

Background: In hereditary transthyretin (ATTRv) amyloidosis, axonal neuropathy is the main pathologic basis of polyneuropathy. However, whether nerve conduction slowing resembling chronic inflammatory demyelinating polyneuropathy (CIDP), observed in some patients, reflects primary demyelination or secondary changes related to axonal damage remains unclear.

Methods: Electrophysiologic findings were compared between 96 patients with V30M ATTRv amyloidosis from nonendemic areas and 175 patients with nutritional or alcoholic axonal neuropathies. Myelinated fiber density was assessed in sural nerve biopsy specimens from 66 and 133 patients, respectively.

Results: Motor nerve conduction velocity (MCV) was reduced and distal motor latency (DML) was prolonged in both groups compared with normal controls, with more marked changes in ATTRv amyloidosis. Compound muscle action potential (CMAP) amplitude and myelinated fiber density were significantly lower in ATTRv amyloidosis than in nutritional/alcoholic neuropathies (p < 0.001). Conduction slowing fulfilling EAN/PNS CIDP criteria was observed only in patients with severe axonal loss. After adjusting for age, disease duration, and CMAP amplitude, only MCV slowing and DML prolongation in median nerve remained more pronounced in ATTRv amyloidosis.

Conclusions: CIDP-like conduction slowing in ATTRv amyloidosis largely represents secondary changes caused by axonal degeneration, although additional mechanisms may contribute to slowing in the median nerve.

Aims: We sought to investigate the prevalence of Transthyretin amyloid (ATTR) deposits in the carpal ligament of patients undergoing surgery for carpal tunnel syndrome (CTS) and the frequency of concomitant ATTR-cardiomyopathy (CM) in a prospective study with long-term follow-up.

Methods and results: Our prospective exploratory study enrolled 551 patients treated for CTS. All resection specimens of carpal ligament underwent histopathological evaluation. Patients with confirmed amyloid deposits were referred to cardiac evaluation, including cardiac MRI (CMR) scans, as well as follow-up examinations. Amyloid deposits were found in 52 (9%) specimens (1 light chain amyloid, 51 ATTR). Among patients with positive biopsy ATTR-CM was diagnosed in 4 (8%) patients, 1 patient was diagnosed at initial evaluation, and 3 patients were diagnosed during the follow-up. All patients had ATTRwt at an early stage of disease. Extracellular volume (ECV) measured by CMR was significantly higher in amyloid-positive CTS patients compared to healthy controls (30 ± 2 vs. 24 ± 1%, p < .01).

Conclusion: Histopathological evaluation of resected carpal ligament should be considered in patients at least older than 70 years. Even though absolute numbers were low, cardiac screening of patients with evidence of amyloid deposits in in carpal tunnel tissues might facilitate early diagnosis of ATTR-CM in some patients.

Background: Acquired transthyretin (ATTR) amyloidosis is increasingly reported among domino liver transplantation (DLT) recipients who receive livers from patients with hereditary variant TTR (ATTRv) amyloidosis. However, its long-term outcomes and the effects of disease-modifying drugs remain unclear.

Methods: We retrospectively analyzed 30 DLT recipients who received liver grafts from ATTRv amyloidosis patients. Longitudinal evaluations included clinical scores, nerve conduction studies (NCS),¹²³I-metaiodobenzylguanidine scintigraphy, echocardiography, electrocardiography,^99mTc-pyrophosphate scintigraphy, and serum biomarkers.

Results: Overall survival at 1, 3, and 10 years after DLT was 86.7%, 76.7%, and 57.7%, respectively. Amyloid deposition occurred in 17 recipients, with a median time from DLT to deposition of 7.7 years (range, 3.1-9.0 years). Among the 12 patients followed for >3 years after amyloid detection, tafamidis clinically stabilized neuropathy in most cases, however, NCSs revealed progressive subclinical axonal degeneration. Two patients experienced clinically significant neuropathy progression during tafamidis treatment, which was stabilized after switching to siRNA therapy. Clinically significant cardiac amyloidosis developed in only one patient.

Conclusions: Acquired ATTR amyloidosis frequently develops in long-term DLT recipients. Although tafamidis stabilizes clinical manifestations in most patients, it may not completely prevent disease progression in some cases. Further long-term evaluation is needed to determine optimal treatment strategies, including siRNA therapy.

Objective: To evaluate the diagnostic test accuracy of cardiac magnetic resonance (CMR) and echocardiography for diagnosis of cardiac involvement in patients with biopsy proven light-chain (AL) amyloidosis.

Methods: This systematic review addresses late gadolinium enhancement (LGE) on CMR and different echocardiographic findings for cardiac involvement using an acceptable reference standard. Meta-analysis reported sensitivity and specificity with 95% confidence intervals when we have ≥3 studies, or ranges for 2 studies. We assessed certainty of evidence using GRADE (Grading of Recommendations Assessment, Development, and Evaluation).

Results: Seven studies evaluated LGE, yielding pooled sensitivity and specificity of 0.95 (0.87-0.98) and 0.87 (0.76-0.94). Nineteen studies addressed echocardiography. Interventricular septum thickness showed sensitivity of 0.77 (0.69-0.84) and specificity of 0.71 (0.60-0.81). Diastolic dysfunction (grade 2-3) sensitivity was 0.71 (0.40-0.90) and specificity was 0.75 (0.64-0.84); restrictive filling pattern (grade 3) sensitivity was 0.42 (0.28-0.58) and specificity 0.89 (0.83-0.94). E/A ratio sensitivity ranged from 0.45 to 0.65, with specificity from 0.85 to 0.98. Global longitudinal strain sensitivity was 0.86 (0.65-0.95) and specificity was 0.76 (0.55-0.89). Apical sparing pattern showed sensitivity of 0.72 (0.64-0.78) and specificity of 0.78 (0.64-0.88). Certainty of evidence was very low.

Conclusion: CMR might be more accurate than echocardiography for diagnosis of cardiac involvement in AL amyloidosis.