Amyloid-Journal of Protein Folding Disorders最新文献

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 β₂-microglobulin-related amyloids (Aβ2M amyloid). To inhibit DRA progression, hexadecyl-immobilized cellulose bead (HICB) columns are employed to adsorb circulating β₂-microglobulin (β2M). 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 Aβ2M 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 β2M, lysozyme, angiogenin, complement factor D and matrix Gla protein were reduced. These proteins acted in the Aβ2M 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 Aβ2M amyloidogenesis by reducing the amyloid-related proteins.

Background: Neurofilament light chain (NfL) has emerged as a sensitive biomarker in hereditary transthyretin amyloid polyneuropathy (ATTRv-PN). We hypothesise that NfL can identify conversion of gene carriers to symptomatic disease, and guide treatment approaches.

Methods: Serum NfL concentration was measured longitudinally (2015-2022) in 59 presymptomatic and symptomatic ATTR variant carriers. Correlations between NfL and demographics, biochemistry and staging scores were performed as well as longitudinal changes pre- and post-treatment, and in asymptomatic and symptomatic cohorts. Receiver-operating analyses were performed to determine cut-off values.

Results: NfL levels correlated with examination scores (CMTNS, NIS and MRC; all p < .01) and increased with disease severity (PND and FAP; all p < .05). NfL was higher in symptomatic and sensorimotor converters, than asymptomatic or sensory converters irrespective of time (all p < .001). Symptomatic or sensorimotor converters were discriminated from asymptomatic patients by NfL concentrations >64.5 pg/ml (sensitivity= 91.9%, specificity = 88.5%), whereas asymptomatic patients could only be discriminated from sensory or sensorimotor converters or symptomatic individuals by a NfL concentration >88.9 pg/ml (sensitivity = 62.9%, specificity = 96.2%) However, an NfL increment of 17% over 6 months could discriminate asymptomatic from sensory or sensorimotor converters (sensitivity = 88.9%, specificity = 80.0%). NfL reduced with treatment by 36%/year and correlated with TTR suppression (r = 0.64, p = .008).

Conclusions: This data validates the use of serum NfL to identify conversion to symptomatic disease in ATTRv-PN. NfL levels can guide assessment of disease progression and response to therapies.

Background: Transthyretin cardiac amyloidosis (ATTR cardiac amyloidosis) is caused by variant (ATTRv) or wild type (ATTRwt) transthyretin. While gait abnormalities have been studied in younger patients with ATTRv amyloidosis, research on gait in older adults with ATTR cardiac amyloidosis is lacking. Given ATTR cardiac amyloidosis' association with neuropathy and orthopedic manifestations, we explore the gait in this population.

Methods: Twenty-eight older male ATTR cardiac amyloidosis patients and 11 healthy older male controls walked overground with and without a dual cognitive task. Gait parameters: stride width, length, velocity and stance time percentage were measured using an instrumented mat. ATTR amyloidosis patients were further categorized based on clinical and functional assessments.

Results: We found significant gait differences between ATTR cardiac amyloidosis patients and healthy controls; patients had more variable, slower, narrower and shorter strides, with their feet spending more time in contact with the ground as opposed to in swing. However, the observed gait differences did not correlate with clinical and functional measures of ATTR cardiac amyloidosis severity.

Conclusions: Our results suggest that gait analysis could be a complementary tool for characterizing ATTR cardiac amyloidosis patients and may inform clinical care as it relates to falls, management of anticoagulation, and functional independence.

Background: AL amyloidosis (AL) results from the misfolding of immunoglobulin light chains (IG LCs). Aim of this study was to comprehensively analyse kappa LC sequences from AL patients in comparison with multiple myeloma (MM).

Objective: We analysed IGKV/IGKJ usage and associated organ tropism and IGKV1/D-33 in terms of mutational analysis and theoretical biochemical properties.

Material and methods: cDNA and bulk RNA sequencing of the LCs of AL and MM patients.

Results: We studied 41 AL and 83 MM patients showing that IGKV1 was most expressed among kappa AL and MM, with higher frequency in AL (80% vs. 53%, p = .002). IGKV3 was underrepresented in AL (10% vs. 30%, p = .014). IGKJ2 was more commonly used in AL than in MM (39% vs. 29%). Patients with IGKV1/D-33 were associated with heart involvement (75%, p = .024). IGKV1/D-33-segments of AL had a higher mutation count (AL = 12.0 vs. MM = 10.0). FR3 and CDR3 were most frequently mutated in both, with a median mutation count in FR3 being the highest (AL = 4.0; MM = 3.5) and one mutation hotspot (FR3 (83I)) for IGKV1/D-33/IGKJ2 was associated with cardiac involvement.

Conclusion: This study confirmed that germline usage has an influence on AL amyloidosis risk and organ involvement.

Background: Technetium-99m-pyrophosphate (^99mTc-PYP) uptake in the internal oblique muscle (IOM), which is often observed in patients with wild-type transthyretin cardiac amyloidosis (ATTR-CA), indicates amyloid transthyretin (ATTR) deposition.

Objective: This study aimed to assess the safety and efficacy of ^99mTc-PYP imaging-based computed tomography (CT)-guided core-needle biopsy of the IOM as a new extracardiac screening biopsy for confirming the presence of ATTR deposits.

Methods: Patients with suspected ATTR-CA in whom myocardial tracer uptake was detected on chest- and abdomen-centered images of ^99mTc-PYP scintigraphy underwent CT-guided core-needle biopsy at the site with the highest tracer uptake in the IOM between September 2021 and November 2022.

Results: All 18 consecutive patients (mean age, 86.3 years ± 6.5; 61.1% male) enrolled in the study showed ^99mTc-PYP uptake into the IOM. Adequate tissue samples were obtained from all patients except one without serious complications. Immunohistochemical analysis confirmed ATTR deposits in 16/18 (88.9%) patients. In the remaining two patients, ATTR deposits were observed via endomyocardial biopsy. All patients were diagnosed with wild-type ATTR-CA based on transthyretin gene sequence testing results.

Conclusion: In wild-type ATTR-CA, ^99mTc-PYP imaging-based CT-guided core-needle biopsy of the IOM could be used as an extracardiac screening biopsy to confirm the presence of ATTR deposits.