The relationship between amyloidosis and vasculature in cognitive impairment and Alzheimer\'s disease (AD) pathogenesis is increasingly acknowledged. We conducted a quantitative and topographic assessment of retinal perivascular amyloid plaque (AP) distribution in individuals with both normal and impaired cognition. Using a retrospective dataset of scanning laser ophthalmoscopy fluorescence images from twenty-eight subjects with varying cognitive states, we developed a novel image processing method to examine retinal peri-arteriolar and peri-venular curcumin-positive AP burden. We further correlated retinal perivascular amyloidosis with neuroimaging measures and neurocognitive scores. Our study unveiled that peri-arteriolar AP counts surpassed peri-venular counts throughout the entire cohort (P < 0.0001), irrespective of the primary, secondary, or tertiary vascular branch location, with a notable increase among cognitively impaired individuals. Moreover, secondary branch peri-venular AP count was elevated in the cognitively impaired (P < 0.01). Significantly, peri-venular AP count, particularly in secondary and tertiary venules, exhibited a strong correlation with clinical dementia rating, Montreal cognitive assessment score, hippocampal volume, and white matter hyperintensity count. In conclusion, our exploratory analysis detected greater peri-arteriolar versus peri-venular amyloidosis and a marked elevation of amyloid deposition in secondary branch peri-venular regions among cognitively impaired subjects. These findings underscore the potential feasibility of retinal perivascular amyloid imaging in predicting cognitive decline and AD progression. Larger longitudinal studies encompassing diverse populations and AD-biomarker confirmation are warranted to delineate the temporal-spatial dynamics of retinal perivascular amyloid deposition in cognitive impairment and the AD continuum.

Systemic diseases can cause heart block owing to the involvement of the myocardium and thereby the conduction system. Younger patients (<60) with heart block should be evaluated for an underlying systemic disease. These disorders are classified into infiltrative, rheumatologic, endocrine, and hereditary neuromuscular degenerative diseases. Cardiac amyloidosis owing to amyloid fibrils and cardiac sarcoidosis owing to noncaseating granulomas can infiltrate the conduction system leading to heart block. Accelerated atherosclerosis, vasculitis, myocarditis, and interstitial inflammation contribute to heart block in rheumatologic disorders. Myotonic, Becker, and Duchenne muscular dystrophies are neuromuscular diseases involving the myocardium skeletal muscles and can cause heart block.

UNASSIGNED: Transthyretin amyloid cardiomyopathy (ATTR-CM) is a fatal disease. Tafamidis was approved to treat patients with ATTR-CM based on findings from the ATTR-ACT (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial).
UNASSIGNED: This post hoc analysis examined the proportion of patients who experienced improved efficacy measures through 30 months of treatment with tafamidis or placebo in ATTR-ACT.
UNASSIGNED: Patients with ATTR-CM were randomized to tafamidis (80 mg or 20 mg) or placebo. Change from baseline in 6-minute walk test distance, Kansas City Cardiomyopathy Questionnaire Overall Summary score, N-terminal pro-B-type natriuretic peptide concentration, patient global assessment of overall health, and New York Heart Association functional class were assessed at regular time points. The proportion of patients with improvement was summarized for each time point with odds ratio. Missing data were imputed as deterioration.
UNASSIGNED: Higher proportions of tafamidis-treated patients (n = 264) than placebo-treated patients (n = 177) showed improvement in all assessments. The odds ratio for improvement favored tafamidis for all measures and at all time points. It was significant (P < 0.001) at month 30 for 6-minute walk test distance (4.9; 95% CI: 2.28-10.69), Kansas City Cardiomyopathy Questionnaire Overall Summary score (3.3; 95% CI: 1.85-5.78), N-terminal pro-B-type natriuretic peptide concentration (5.3; 95% CI: 2.66-10.73), and patient global assessment of overall health (2.9; 95% CI: 1.69-4.95).
UNASSIGNED: This analysis found that higher proportions of patients treated with tafamidis experienced improvement from baseline in measures of heart failure, functional capacity, and health-related quality of life than those treated with placebo during ATTR-ACT. These data provide further evidence of the clinical benefits of tafamidis in patients with ATTR-CM. (Safety and Efficacy of Tafamidis in Patients With Transthyretin Cardiomyopathy [ATTR-ACT]; NCT01994889).

UNASSIGNED: Cardiac amyloidosis can coexist in patients with severe aortic stenosis. There are limited outcomes data on whether this impacts the risk of transcatheter aortic valve replacement (TAVR).
UNASSIGNED: The authors aimed to investigate the effect of amyloidosis on outcomes of TAVR.
UNASSIGNED: We used the Nationwide Readmissions Database to identify hospitalizations for TAVR between 2016 and 2019. The presence of a diagnosis of amyloidosis was identified. Propensity score-weighted regression analysis was used to identify the association of amyloidosis with in-hospital mortality, acute ischemic stroke, and 30-day readmission rate after TAVR.
UNASSIGNED: We identified 245,020 hospitalizations for TAVR, including 273 in patients with amyloidosis. The mean age was 79.4 ± 8.4 years. There was no difference in in-hospital mortality or 30-day readmission rate in patients with and without amyloidosis (1.8% vs 1.5%, P = 0.622; and 12.9% vs 12.5%, P = 0.858; respectively). However, there was a higher rate of acute ischemic stroke in patients with amyloidosis (6.2% vs 1.8%, P < 0.001). Propensity score-weighted logistic regression analysis showed the presence of amyloidosis was associated with greater odds of acute ischemic stroke (odds ratio: 3.08, 95% CI: 1.41-6.71, P = 0.005), but no difference in mortality (odds ratio: 0.79, 95% CI: 0.28-2.27, P = 0.666) or 30-day readmission rate after TAVR (HR: 0.72, 95% CI: 0.41-1.25, P = 0.241).
UNASSIGNED: This analysis suggests amyloidosis may be associated with a higher thromboembolic risk after TAVR that merits further investigation.

暂无摘要。

OBJECTIVE: Our purpose was to compare differences in the incidence of amyloid deposition in tenosynovium (TS) versus transverse carpal ligament (TCL) biopsies obtained during open carpal tunnel release. We hypothesized that the incidence of amyloid would be similar between TCL and TS when obtaining both specimens from the same patient.
METHODS: All primary, elective open carpal tunnel release cases that underwent biopsy for amyloid between January 2022 and September 2023 were reviewed. Tenosynovial and TCL specimens were independently evaluated by a pathologist to assess for amyloid. Demographic data were collected, and incidence of amyloid deposition was compared between the two samples. Agreement statistics, sensitivity, and specificity were calculated for TCL, using TS as the reference standard.
RESULTS: A total of 196 cases met either Tier 1 (n=180) or Tier 2 (n=16) biopsy criteria. Forty-eight cases were excluded for missed biopsies or laboratory processing errors, leaving 148 cases available for analysis. Amyloid deposition was present in 31 out of 148 (21%) TS specimens and 33 out of 148 (22%) TCL specimens. Overall, the results of the TS biopsy agreed with TCL biopsy in 138 out of 148 cases (93%). In the 10 cases for which the results of the TCL and TS biopsy differed, six cases had (+) TCL and (-) TS, and four cases had amyloid deposition in TS without evidence of deposition in the TCL. Sensitivity and specificity values for the TCL specimen were 87% and 95%, respectively. Positive and negative predictive values were 82% and 97%, respectively.
CONCLUSIONS: For cases of open carpal tunnel release undergoing biopsy, amyloid deposition was noted in 21% of TS specimens and 22% of TCL specimens. Results of TS and TCL biopsies obtained from the same patient agreed in 93% of cases. Single-source biopsy for amyloid represents a reasonable diagnostic approach. Future cost analyses should be performed to determine whether the addition of two biopsy sources to improve diagnostic accuracy is justified.
METHODS: Prognostic II.

Background: The accruing evidence about the efficacy of anti-IL-1 agents in Familial Mediterranean Fever (FMF) patients led to their widespread off-label use. Therefore, identifying precise indications and clinical characteristics of IL-1i-warranting patients are important. This study investigated the clinical characteristics and treatment indications of patients with FMF requiring interleukin 1 inhibition therapy (IL-1i). Methods: Hospital records of FMF patients attending a tertiary care center at the Department of Rheumatology, University of Health Sciences, Basaksehir Cam and Sakura City Hospital were retrospectively analyzed. Data on symptoms and disease manifestations, age of symptom onset, time to diagnosis, MEFV variants, type of treatment, and their indications were collected. Results: Between June 2020 and March 2023, 312 FMF patients were identified. The mean age at the onset of symptoms was 14.0, and the mean time to diagnosis was 11.9 years. In total, 87.1% of patients were receiving colchicine monotherapy, while the remaining 11.8% warranted IL-1i. Clinical symptoms and flare manifestations did not show a significant difference between the two groups. However, patients receiving IL-1i started having symptoms at younger age (11.5 vs. 14.5, p = 0.042) and time to diagnosis was longer (18.2 vs. 11.0, p < 0.01). M694V homozygosity was more common in patients receiving IL-1i. Indications for patients receiving IL-1i were colchicine resistance (8.0%), secondary amyloidosis (5.1%), and colchicine intolerance (2.2%). Conclusions: This study shows that a subset of FMF patients, particularly those with a more severe phenotype with an earlier disease onset and M694V homozygosity, require IL-1i treatment despite the overall good efficacy and tolerability of colchicine, primarily due to colchicine resistance, intolerance, or complications such as amyloidosis.

Serum amyloid A (SAA) proteins are highly conserved lipoproteins that are notoriously involved in the acute phase response and systemic amyloidosis, but their biological functions are incompletely understood. Recent work has shown that SAA proteins can enter the brain by crossing the intact blood-brain barrier (BBB), and that they can impair BBB functions. Once in the central nervous system (CNS), SAA proteins can have both protective and harmful effects, which have important implications for CNS disease. In this review of the thematic series on SAA, we discuss the existing literature that relates SAA to neuroinflammation and CNS disease, and the possible roles of the BBB in these relations.

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease that affects the motoneurons. More than 40 genes are related with ALS, and amyloidogenic proteins like SOD1 and/or TDP-43 mutants are directly involved in the onset of ALS through the formation of polymorphic fibrillogenic aggregates. However, efficacious therapeutic approaches are still lacking. Notably, heterozygous missense mutations affecting the gene coding for RNase 5, an enzyme also called angiogenin (ANG), were found to favor ALS onset. This is also true for the less-studied but angiogenic RNase 4. This review reports the substrate targets and illustrates the neuroprotective role of native ANG in the neo-vascularization of motoneurons. Then, it discusses the molecular determinants of many pathogenic ANG mutants, which almost always cause loss of function related to ALS, resulting in failures in angiogenesis and motoneuron protection. In addition, ANG mutations are sometimes combined with variants of other factors, thereby potentiating ALS effects. However, the activity of the native ANG enzyme should be finely balanced, and not excessive, to avoid possible harmful effects. Considering the interplay of these angiogenic RNases in many cellular processes, this review aims to stimulate further investigations to better elucidate the consequences of mutations in ANG and/or RNase 4 genes, in order to achieve early diagnosis and, possibly, successful therapies against ALS.

Transthyretin (TTR) is a homotetrameric protein involved in the transport of thyroxine. More than 150 different mutations have been described in the TTR gene, several of them associated with familial amyloid cardiomyopathy (FAC). Recently, our group described a new variant of TTR in Brazil, namely A39D-TTR, which causes a severe cardiac condition. Position 39 is in the AB loop, a region of the protein that is located within the thyroxine-binding channels and is involved in tetramer formation. In the present study we solved the structure and characterize the thermodynamic stability of this new variant of TTR using urea and high hydrostatic pressure (HHP). Interestingly, during the process of purification, A39D-TTR turned out to be a dimer and not a tetramer, a variation that might be explained by the close contact of the four aspartic acids at position 39, where they face each other inside the thyroxine channel. In the presence of sub-denaturing concentrations of urea, bis-ANS binding and dynamic light scattering revealed A39D-TTR in the form of a molten-globule dimer. Co-expression of A39D and WT isoforms in the same bacterial cell did not produce heterodimers or heterotetramers, suggesting that somehow a negative charge at the AB loop precludes tetramer formation. A39D-TTR proved to be highly amyloidogenic, even at mildly acidic pH values where WT-TTR does not aggregate. Interestingly, despite being a dimer, aggregation of A39D-TTR was inhibited by diclofenac, which binds to the thyroxine channel in the tetramer, suggesting the existence of other pockets in A39D-TTR able to accommodate this molecule.