Amyloid-Journal of Protein Folding Disorders最新文献

The peripheral nervous system (PNS) is commonly affected in immunoglobulin light chain amyloid protein (AL) amyloidosis. PNS involvement and particularly small fiber neuropathy (SFN) is often clinically underestimated, requiring a standardized approach for comprehensive assessment. We prospectively evaluated the prevalence and clinical significance of SFN in 81 patients with newly diagnosed AL amyloidosis using clinical examination, nerve conduction studies (NCSs), quantitative sensory testing (QST) examination and distal-leg skin biopsy. Neuropathy was detected in 89% of patients and SFN in 65%. Combined small and large fiber neuropathy was seen in 48.1%, pure large fiber neuropathy in 20% and pure SNF in 10%. Older age was a significant risk factor for SFN (OR 1.06, 95% CI 1.01-1.12, p = .014); patients with SFN were also more likely to have soft tissue involvement (OR 7.1, 95% CI 1.5-33.4, p = .013). After a median follow-up of 37.5 months, SFN was associated with poorer overall survival (OS) and it emerged as an independent prognostic factor for early mortality (<12 months) in multivariate analysis (HR 4.3 95% CI 1.23-15.04, p = .023). Our study demonstrates the high prevalence and clinical significance of SFN as an adverse factor for survival and indicates the need for multiparametric neurological evaluation in patients with AL amyloidosis at diagnosis.

Background: We explored sex differences in wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) and determined survival and prognostic factors.

Methods: In a retrospective cohort study at a reference centre in France from 1 January 2008 to 31 December 2022, multiple regression analyses, supervised clustering, Cox models, and a Kaplan-Meier analysis were used to compare women and men in each age quartile (Q1: ≤77 years; Q2: 78-82; Q3: 83-86; Q4 > 86).

Results: We included 1062 patients with ATTRwt-CM (180 women, 16%). The women had a higher median [IQR] left ventricular ejection fraction (LVEF; 52% [45-60] vs. 50 [43-58] in men) and a thinner interventricular septum. 12% of women and 4.1% of men had a septum thickness <12 mm (p = 0.004). The women in Q1 had lower LVEF and global longitudinal strain values and a higher prevalence of a septum <12 mm (15.8%, vs 2.0% in men) than men and older women (Q2-Q3-Q4). Women had a greater risk of sudden death than men (13.8% vs. 4.6%, respectively; odds ratio [95% confidence interval]: 3.24 [1.56-6.64]; p = 0.001).

Conclusions: In women, the ATTRwt-CM phenotype and prognosis are related to age at diagnosis. Decreasing the septum thickness cut-off would increase the frequency of ATTR-CM diagnosis in women.

Background: We explored the value of myocardial radiomics by computed tomography angiography (CTA) for detection of transthyretin amyloidosis cardiomyopathy (ATTR-CM).

Methods: The study included 589 patients with aortic stenosis and CTA datasets. Radiomics were extracted from LV myocardium. Arm 1 (n = 400) served for method optimisation and removal of redundant features. In Arm 2 (n = 30), we identified radiomics associated with extracellular volume by CT (ECV_CT); in Arm 3 (n = 159), radiomics were compared in patients with/without positive bone scintigraphy scan (training cohort, n = 84; validation cohort, n = 75) to build a radiomic signature for ATTR-CM.

Results: In Arm 1, unsupervised clustering of patients based on radiomics was associated with significant differences in patients' clinical profile among clusters. In Arm 2, we constructed a radiomic-based ECV (correlation with ECV_CT: rho = .78, p = 1.2 x 10^-6) with excellent diagnostic accuracy for high ECV_CT (AUC = .925, 95%CI: .825-1.000, p = .0002). In Arm 3, a radiomic score (AmyloidRS) had good performance for ATTR-CM detection in the training (c-index .88, 95%CI: .80-.95) and validation cohort (c-index .84, 95%CI: .69-.98). When combined with clinical features, AmyloidRS maximised diagnostic accuracy for ATTR (kappa: .894, balanced accuracy .984).

Conclusions: We present a radiomic method for myocardial tissue characterisation in patients with severe aortic stenosis which enables ATTR-CM detection from standard CTA scans.

Organ response is key to improving outcomes in light chain (AL) amyloidosis. We investigated factors associated hepatic response (HepR) in a large cohort of patients with hepatic AL amyloidosis.

Methods: Retrospective study of newly-diagnosed AL amyloidosis patients (n = 130) with liver involvement evaluated at the Mayo Clinic between 2000-2021. Patients were eligible if they had documented liver involvement and baseline alkaline phosphatase (ALP)≥1.5x upper limit of normal (ULN). HepR was defined as >50% reduction in ALP from baseline or ALP normalization. HepRs were assessed at 6, 12, 24 month after treatment initiation and the best HepR at any time point.

Results: The median baseline ALP was 2.88-fold the ULN (ALP:ULN, IQR: 2.15-4.41), and the median bilirubin was 0.7 mg/dL. HepR rates increased with time from 28% at 6 months, 36% at 12 months and 48% at 24 months. The median time to HepR was 21.5 months (95%CI = 15.4-29.5). Baseline ALP ≥ 4xULN consistently predicted HepR across all time points. Hematological response (HemR) also independently predicted HepR at 12, 24 months and best response. At best hepatic response, kappa isotype, and front-line ASCT were further independent predictors of HepR.

Conclusions: The degree of baseline ALP elevation and HemR are reliable predictors of HepR.

Background: Wild-type transthyretin (ATTRwt) amyloidosis is underdiagnosed and generally diagnosed with manifest cardiac involvement. Lumbar spinal stenosis (LSS) might be an early sign of systemic transthyretin amyloidosis and a possible screening target for early diagnosis.

Objectives: To assess the prevalence of cardiac amyloidosis (CA) 6 years post-LSS surgery, among patients with transthyretin amyloid deposits in ligamentum flavum.

Methods: Twenty-one patients who had surgery for LSS in 2016-2018 and grade 3-4 ATTR amyloid deposits in ligamentum flavum were followed up in 2022-2023, including biomarkers, echocardiography, cardiac magnetic resonance (CMR) and nuclear imaging.

Results: At follow-up, median age was 79 years, 16% (3/19) displayed cardiac uptake on scintigraphy consistent with ATTR-CA. Forty-eight percent (10/21) had a history of other tenosynovial conditions associated with ATTRwt. We observed a small increase in tissue characteristics using CMR, and a decrease in left ventricular global longitudinal strain and left atrial strain on echocardiography.

Conclusions: In this prospective cohort study, 16% were diagnosed with ATTRwt cardiomyopathy, six years following surgery for LSS. History of other tenosynovial conditions associated with ATTRwt amyloidosis was common. These findings strengthen the hypothesis that LSS is a possible manifestation of ATTRwt amyloidosis and that in selected patients with LSS, cardiac follow-up is of value.

Background: Hereditary transthyretin amyloidosis (ATTRv) is a life-threatening, but treatable disease presenting with autonomic dysfunction. This study investigates the progression of autonomic failure, response to treatment, and the impact of autonomic failure in ATTRv.

Methods: Clinical features and autonomic function test (AFT) results were evaluated in 126 patients (40 had treatment) and 12 asymptomatic TTR variant carriers. A subgroup had follow-up (FU) AFT. Kaplan-Meier estimates compared survival time between participants with and without neurogenic orthostatic hypotension (nOH), and logistic regression assessed its impact on mortality.

Results: Patients treated early with disease modifying therapies (DMT) had slower progression and did not develop nOH. In 59 individuals with repeat AFT, autonomic dysfunction worsened, with a decline in the Valsalva ratio (p = 0.002), even in early-stage disease (p = 0.019; median disease duration at FU 4 years). nOH at first assessment predicted worse outcome (mean survival time in individuals with nOH 7.0 vs. 14.9 years without nOH, p < 0.001) and death (OR = 5.27; 95%CI: 1.94 - 14.31; p = 0.001).

Conclusions: The early development of autonomic dysfunction and nOH is an independent predictive factor for shorter survival in ATTRv. Autonomic testing is a valuable biomarker to capture disease progression. Prospective studies need to confirm the benefit of DMT on autonomic dysfunction.