Pharmacodynamic evaluation and safety assessment of treatment with antibodies to serum amyloid P component in patients with cardiac amyloidosis: an open-label Phase 2 study and an adjunctive immuno-PET imaging study.

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).

Assessment of neuroinflammation in a mouse model of obesity and ß-amyloidosis using PET.

BACKGROUND: Obesity has been identified as a risk factor for cognitive decline and Alzheimer's disease (AD). The aim of this study was to investigate the effect of obesity on neuroinflammation and cerebral glucose metabolism using PET in a mouse model of ß-amyloidosis and determine the relationship between these PET imaging biomarkers, pathogenic changes, and functional outcomes. METHODS: Three-month-old C57BL/J6 mice were fed either a standard (control group) or high-fat diet (obese group) for 3 months and intracerebroventricularly infused with vehicle or human beta amyloid 1-42 (Aß42). We assessed obesity-induced abnormalities in peripheral metabolic indices including adiposity, fasting glucose, and glucose tolerance. Brain glucose metabolism was assessed by (18)F-FDG PET, and glial activation was assessed using the translocator protein (TSPO) ligand (11)C-PBR-28. TSPO expression was confirmed by immunohistochemistry of brain sections obtained from scanned mice. The association between inflammatory state and (11)C-PBR-28 PET signals was characterized by examination of the cytokine expression profile in both the serum and hippocampus by antibody array. Learning and memory performance was assessed in the object recognition task, and anxiety-related behavior was assessed in the elevated plus maze. RESULTS: Obesity combined with Aß infusion promoted neuroinflammation and cerebral hypermetabolism, and these signals were significant predictors of learning and memory performance in the object recognition task. In vivo TSPO signals were associated with inflammatory markers including CXCL1, CXCL2, CXCL12, CCL3, CCL5, TIMP-1, G-CSF, sICAM-1, and IL-1ra. CONCLUSIONS: In vivo cerebral metabolism and TSPO signals indicate that obesity can accelerate amyloid-induced inflammation and associated cognitive decline.

Regional myocardial microvascular dysfunction in cardiac amyloid light-chain amyloidosis: assessment with 3T cardiovascular magnetic resonance.

BACKGROUND: Coronary microvascular dysfunction is highly prevalent in patients with amyloid light-chain (AL) cardiac amyloidosis (AL-CA). The aim of this study was to clarify the feasibility of first-pass perfusion imaging using 3 T cardiovascular magnetic resonance (CMR) for evaluating the difference in left ventricular (LV) regional myocardial microvascular function among normal subjects and in patients with AL-CA. The amyloidosis patients were classified into those with impaired systolic function [LV ejection fraction (LVEF) < 50 %] and those with preserved systolic function. METHODS: In total, 32 patients with biopsy-proven AL-CA, including 11 AL-CA patients with systolic dysfunction, 21 AL-CA patients with preserved systolic function, and 25 healthy subjects, underwent CMR examination. LV regional myocardial perfusion parameters included upslope, time to maximum signal intensity (TTM) and max signal intensity (MaxSI) were compared among the three patient groups. Receiver operating characteristic analysis was performed to determine whether perfusion parameters could be used in discriminating regional myocardial microvascularity between AL-CA patients and normal subjects. RESULTS: The patients with AL-CA had significantly reduced first-pass perfusion upslope and MaxSI, and increased TTM compared with the normal subjects (all P < 0.01). Compared with the patients with AL-CA and preserved LVEF, the patients with AL-CA and impaired systolic function had a longer TTM in the basal (47.05 ± 16.59 vs. 39.68 ± 19.11; P = 0.002) and mid-ventricular (44.61 ± 16.34 vs. 37.74 ± 18.25; P = 0.002) segments; lower upslope in the basal (2.41 ± 1.32 vs. 3.60 ± 1.68; P < 0.0001), mid-ventricular (2.82 ± 1.34 vs. 4.15 ± 2.02; P < 0.0001), and apical (3.71 ± 1.38 vs. 4.97 ± 2.55; P = 0.004) segments; and lower MaxSI (31.67 ± 15.23 vs. 37.96 ± 11.15; P < 0.0001) in the basal segment. The ROC curve analysis revealed that the first-pass upslope, TTM, and MaxSI may be used as indicators for differentiating microcirculation between AL-CA patients with preserved or impaired systolic function and normal subjects. CONCLUSIONS: The differences in LV regional myocardial microvascular function among normal subjects, AL-CA patients with systolic dysfunction, and AL-CA patients with preserved systolic function can be monitored using first-pass perfusion CMR.

Improvement of risk assessment in systemic light-chain amyloidosis using human placental growth factor.

BACKGROUND: Vascular amyloid deposition is common in light-chain amyloidosis resulting in endothelial dysfunction. Human placental growth factor (PlGF), a member of the vascular endothelial growth factor family was found to be altered in diverse pathological conditions, e.g. endothelial dysfunction. This study evaluated the clinical role of PlGF in light-chain amyloidosis. METHODS: PlGF (cobas-PlGF, Roche Diagnostics, Mannheim, Germany) was analyzed in 125 consecutive patients with AL and correlated with diverse clinical parameters including mortality. RESULTS: Kidney (n = 76) and heart (n = 57) were predominantly affected by amyloid deposition. Median PlGF was 26.3 (21.1-42.1) ng/L, NT-proBNP 3649 (1124-8581) pg/mL, and hs-TnT 42 (21-107) ng/L. PlGF increased with number of organs involved and with deterioration of renal function. A significant correlation of PlGF with hs-TnT (ρ = 0.306; p = 0.0007) and NT-proBNP (ρ = 0.315; p = 0.0006) was observed, but no correlation was observed with clinical, echocardiography, and electrocardiography parameters of cardiac involvement. In this cohort 1-year all-cause mortality was 19.2 %. The best cutoff discriminating survivors and non-survivors was 28.44 ng/L (sensitivity 66.7 %; specificity 78.1 %). A three-step risk model including hs-TnT and NT-proBNP revealed a better discrimination if patients at intermediary risk were additionally stratified by PlGF. Net reclassification index was 37.2 % (p = 0.002). Multivariate analysis revealed PlGF, difference of involved and uninvolved light chain, number of organs involved and risk class according to troponin T and NT-proBNP as independent predictors of mortality. CONCLUSION: Plasma PlGF values in AL are invariably associated with the number of involved organs, but not with clinical, echocardiography, and electrocardiography parameters of cardiac involvement. PlGF provide useful information for risk stratification of patients at intermediary risk according to hs-TnT and NT-proBNP.

An immunologic assessment of brain-associated IgG in senile cerebral amyloidosis.

Frontal and occipital lobes were taken within four hours of death from four senile patients (77-94 years) and frozen at -70 degrees C. After thawing at room temperature, gray and white matter were separated and subjected to sequential elution at pH 7.4 and pH 2.5. The eluates were processed for isoelectric focusing on 2.5% polyacrylamide gels and stained with silver nitrate; immunoblotting was done on agarose gels and stained by immunoperoxidase for IgG and light chains. Quantitation of the amount of IgG present in neutral and acidic eluates was performed by immunonephelometry and ELISA. Only the neutral eluates contained significant amounts of IgG, which were usually polyclonal. These data indicate that IgG associated with senile cerebral amyloid are not bound to any brain or vascular component and the data do not support the occurrence of an intraparenchymal immune response.