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Malnutrition is associated with mortality and impaired quality of life (QoL) in systemic immunoglobulin light-chain (AL) amyloidosis. The aim of this study was to determine whether nutritional counseling is beneficial to patients with AL. In this intervention study (ClinicalTrials.gov Identifier: NCT02055534), 144 treatment-naïve outpatients with AL were randomized to usual care (UC; n = 72) and nutritional counseling (NC; n = 72). In the randomized population, although patients in the NC group maintained a stable body weight (weight loss [WL] = 0.6 kg; 95% confidence interval [CI], −1.0 to 2.1; P = 0.214), those in the UC group demonstrated a significant decrease (WL = 2.1 kg; 95% CI, 0.2–4.1; P = 0.003). However, the difference in weight between groups was not significant (mean WL difference = 1.6 kg; 95% CI, −0.7 to 3.9; P = 0.179). Patients in the NC group demonstrated more satisfactory energy intake (≥75% of estimated requirements, odds ratio, 2.18; 95% CI, 1.04–4.57; P = 0.048) and a significant increase in the mental component summary of QoL (Short form-36) at 12 mo (mean difference, 8.1; 95% CI, 2.3–13.9; P = 0.007), which was restored to a mean score of 53 (95% CI, 50–53), over the healthy population norms. NC was also associated with better survival (crude hazard ratio, 0.57; 95% CI, 0.35–0.94; P = 0.028). In outpatients with AL, NC was helpful in preserving body weight, effective in improving mental QoL, and associated with better survival. •We investigated whether nutritional counseling is beneficial to patients with systemic immunoglobulin light-chain amyloidosis.•Nutritional counseling was helpful in preserving body weight in these patients.•Nutritional counseling was effective in improving the mental quality of life of these patients.•Nutritional counseling was associated with better survival in patients with systemic immunoglobulin light-chain amyloidosis.

Background Few studies have been conducted on the long-term prognosis of patients with amyloid light chain (AL) and amyloid A (AA) renal amyloidosis in the same cohort. Methods We retrospectively examined 68 patients with biopsy-proven renal amyloidosis (38 AL and 30 AA). Clinicopathological findings at the diagnosis and follow-up data were evaluated in each patient. We analyzed the relationship between clinicopathological parameters and survival data. Results Significant differences were observed in several clinicopathological features, such as proteinuria levels, between the AL and AA groups. Among all patients, 84.2 % of the AL group and 93.3 % of the AA group received treatments for the underlying diseases of amyloidosis. During the follow-up period (median 18 months in AL and 61 months in AA), 36.8 % of the AL group and 36.7 % of the AA group developed end-stage renal failure requiring dialysis, while 71.1 % of the AL group and 56.7 % of the AA group died. Patient and renal survivals were significantly longer in the AA group than in the AL group. eGFR of >60 mL/min/1.73 m 2 at biopsy and an early histological stage of glomerular amyloid deposition were identified as low-risk factors. A multivariate analysis showed that cardiac amyloidosis and steroid therapy significantly influenced patient and renal survivals. Conclusions Our results showed that heart involvement was the major predictor of poor outcomes in renal amyloidosis, and that the prognosis of AA renal amyloidosis was markedly better than that in previously reported cohorts. Therapeutic advances in inflammatory diseases are expected to improve the prognosis of AA amyloidosis.

Innate immune memory is a vital mechanism of myeloid cell plasticity that occurs in response to environmental stimuli and alters subsequent immune responses. Two types of immunological imprinting can be distinguished—training and tolerance. These are epigenetically mediated and enhance or suppress subsequent inflammation, respectively. Whether immune memory occurs in tissue-resident macrophages in vivo and how it may affect pathology remains largely unknown. Here we demonstrate that peripherally applied inflammatory stimuli induce acute immune training and tolerance in the brain and lead to differential epigenetic reprogramming of brain-resident macrophages (microglia) that persists for at least six months. Strikingly, in a mouse model of Alzheimer’s pathology, immune training exacerbates cerebral β -amyloidosis and immune tolerance alleviates it; similarly, peripheral immune stimulation modifies pathological features after stroke. Our results identify immune memory in the brain as an important modifier of neuropathology. Peripheral stimuli can induce acute immune training and tolerance in the brain and lead to long-lasting epigenetic reprogramming of microglia; these changes alter pathology in mouse models of stroke and Alzheimer’s pathology .

Systemic light chain amyloidosis (AL)  is a life-threatening disease caused by aggregation and deposition of monoclonal immunoglobulin light chains (LC) in target organs. Severity of heart involvement is the most important factor determining prognosis. Here, we report the 4.0 Å resolution cryo-electron microscopy map and molecular model of amyloid fibrils extracted from the heart of an AL amyloidosis patient with severe amyloid cardiomyopathy. The helical fibrils are composed of a single protofilament, showing typical 4.9 Å stacking and cross-β architecture. Two distinct polypeptide stretches (total of 77 residues) from the LC variable domain (V l ) fit the fibril density. Despite V l high sequence variability, residues stabilizing the fibril core are conserved through different cardiotoxic V l , highlighting structural motifs that may be common to misfolding-prone LCs. Our data shed light on the architecture of LC amyloids, correlate amino acid sequences with fibril assembly, providing the grounds for development of innovative medicines. Immunoglobulin Light Chain Amyloidosis (AL) is the most common systemic amyloidosis occurring in Western countries. Here the authors present the 4.0 Å cryo-EM structure of light chain AL55 fibrils that were isolated from the heart of an AL systemic amyloidosis patient.

Background: Immunoglobulin derived AL amyloidosis and transthyretin derived ATTR amyloidosis are the most common forms of cardiac amyloidosis. Both may present with cardiac arrhythmias, heart failure, and extracardiac symptoms. Disease outcome is often fatal. Recently, it was proposed that amyloid may cause cardiac inflammation. Here we tested the hypothesis that immune cell infiltration in cardiac tissue correlates with clinicopathological patient characteristics. Patients and methods: Myocardial biopsies from 157 patients with cardiac amyloidosis (46.5% AL, 53.3% ATTR) were immunohistochemically assessed for the presence and amount of T lymphocytes (CD3), macrophages (CD68) and neutrophils (MPO). Amyloid load, cardiomyocyte diameter, apoptosis (Caspase 3), necrosis (complement 9), and various clinical parameters were assessed and correlated with immune cell density. Results: Myocardial tissue was infiltrated with T lymphocytes (CD3), macrophages (CD68) and neutrophils (MPO) with variable amounts. Significant correlations were found between the number of macrophages and NYHA class. No correlations were found between the presence and amount of T lymphocytes, neutrophils and clinicopathological patient characteristics. Conclusion: The significant correlation between cardiac macrophage density and heart failure points towards a significant role of macrophages in disease pathology.

Key Points Amyloids can be broadly defined as insoluble protein aggregates containing a characteristic highly ordered, β-sheet-rich structural motif. The latter can be identified histologically with dyes such as Congo Red and thioflavin. Some amyloids may have an adaptive physiological function; however, most amyloids are thought to be abnormal and are associated with a range of clinical pathologies including systemic amyloidoses and some neurodegenerative disorders. Alzheimer's disease, the most common neurodegenerative disorder, is currently the focus of some of the most exciting and rapidly progressing research on amyloid therapeutics. Two main approaches are being pursued to deplete cerebral amyloid β (Aβ) levels, the primary component of senile plaques associated with Alzheimer's disease. The first approach involves inhibition of the secretases responsible for Aβ production. The second approach involves mobilization of the immune system to promote Aβ clearance. Aβ is produced from the sequential proteolysis of amyloid precursor protein (APP) by β- and γ-secretase. The development of small-molecule inhibitors for these enzymes or complexes as a therapeutic method of depleting monomeric Aβ from the brain has met with considerable success, as well as several challenges. Most notably, the secretases have other non-APP substrates (for example, γ-secretase cleavage of Notch and β-secretase cleavage of Neuregulin 1) that are important for normal physiology. Enhanced clearance of monomeric Aβ and Aβ aggregates by Aβ immunotherapy has been used successfully to lower cerebral Aβ levels and promote cognitive improvement in murine amyloid models. Initial attempts to actively immunize against Aβ in humans were suspended owing to the development of adverse immune responses in some patients. However, passive immunotherapeutic approaches have progressed to clinical trials, and administration of intravenous immunglobulins may also be effective for lowering Aβ levels in the brain. Increasing evidence implicates specific forms of Aβ (for example, soluble Aβ oligomers and intraneuronal Aβ) in Alzheimer's disease-associated neurotoxicity, raising the intriguing possibility that therapies targeted at these pools of Aβ (for example, conformation-specific antibodies) may be effective in ameliorating cognitive deficits associated with Alzheimer's disease by blocking cell death pathways rather than altering Aβ homeostasis. Prion diseases are the only known amyloidoses that act as genuine infectious diseases, with the possible exception of AA amyloidosis. The unusual properties of prion amyloid have presented significant challenges for therapeutics, as well as some opportunities to explore unique therapeutic modalities. In many cases of acquired prion disease, prions first colonize and replicate in extraneural secondary lymphoid organs before being transmitted to the central nervous system (CNS). Blockade of prion replication at these extraneural sites (for example, by inhibition of lymphotoxin β receptor (LTβR) signalling) is an effective method to prevent the spread of prions from the periphery to the CNS and may be useful for post-exposure prophylaxis against prion infections. Attempts to generate active immune responses against PrP Sc (PrP with abnormal conformation) have had little success owing to immune tolerance of ubiquitously expressed endogenous PrP C (PrP with normal conformation). However, passive immunization with large doses of PrP antibodies isolated from Prnp −/− mice can prevent the spread of prions from the periphery to the CNS upon intraperitoneal inoculation. It has not yet been demonstrated that PrP immunotherapy is effective in slowing the rate of prion disease once it has reached the CNS. However, the development of PrP antibodies that effectively cross the blood–brain barrier may dramatically enhance the efficacy of PrP immunotherapy for the treatment of CNS prion infections. Numerous compounds have been investigated or are being developed for their anti-aggregation properties including various amyloid-binding dyes, anti-malarial compounds, protein X mimetics, β-sheet breakers and scyllo-inositol. These compounds are still in development for the treatment of prion diseases and other neurodegenerative disorders; however, some of these compounds are currently in clinical trials for the treatment of systemic amyloidoses. Several lines of evidence indicate that protein aggregates trigger specific cellular toxicity pathways in the brain, including the resistance of non-neuronal cell types and Prnp −/− neurons to PrP Sc -induced toxicity. Intriguingly, PrP C was recently identified as a receptor for oligomeric Aβ, suggesting that diverse protein aggregates may activate common neurotoxicity pathways, which may have important therapeutic implications for amyloid diseases. Diseases such as Alzheimer's disease and systemic amyloidoses are associated with inappropriate deposition of proteins containing a characteristic highly ordered, β-sheet-rich structural motif. The common structural and pathogenic features of these diverse protein aggregation diseases may offer opportunities to develop overarching therapeutic strategies. A growing number of diseases seem to be associated with inappropriate deposition of protein aggregates. Some of these diseases — such as Alzheimer's disease and systemic amyloidoses — have been recognized for a long time. However, it is now clear that ordered aggregation of pathogenic proteins does not only occur in the extracellular space, but in the cytoplasm and nucleus as well, indicating that many other diseases may also qualify as amyloidoses. The common structural and pathogenic features of these diverse protein aggregation diseases is only now being fully understood, and may provide novel opportunities for overarching therapeutic approaches such as depleting the monomeric precursor protein, inhibiting aggregation, enhancing aggregate clearance or blocking common aggregation-induced cellular toxicity pathways.

A 58-year-old man presented with a 2-year history of eyelid lesions and several months of weight loss and fatigue. Scattered periorbital petechiae and purpura were noted, as well as coalescing, waxy papules on the eyelids.

In Alzheimer's disease (AD), one of the early responses to Aβ amyloidosis is recruitment of microglia to areas of new plaque. Microglial receptors such as cannabinoid receptor 2 (CB2) might be a suitable target for development of PET radiotracers that could serve as imaging biomarkers of Aβ-induced neuroinflammation. Mouse models of amyloidosis (J20APPswe/ind and APPswe/PS1ΔE9) were used to investigate the cellular distribution of CB2 receptors. Specificity of CB2 antibody (H60) was confirmed using J20APPswe/ind mice lacking CB2 receptors. APPswe/PS1ΔE9 mice were used in small animal PET with a CB2-targeting radiotracer, [11C]A836339. These studies revealed increased binding of [11C]A836339 in amyloid-bearing mice. Specificity of the PET signal was confirmed in a blockade study with a specific CB2 antagonist, AM630. Confocal microscopy revealed that CB2-receptor immunoreactivity was associated with astroglial (GFAP) and, predominantly, microglial (CD68) markers. CB2 receptors were observed, in particular, in microglial processes forming engulfment synapses with Aβ plaques. In contrast to glial cells, neuron (NeuN)-derived CB2 signal was equal between amyloid-bearing and control mice. The pattern of neuronal CB2 staining in amyloid-bearing mice was similar to that in human cases of AD. The data collected in this study indicate that Aβ amyloidosis without concomitant tau pathology is sufficient to activate CB2 receptors that are suitable as an imaging biomarker of neuroinflammation. The main source of enhanced CB2 PET binding in amyloid-bearing mice is increased CB2 immunoreactivity in activated microglia. The presence of CB2 immunoreactivity in neurons does not likely contribute to the enhanced CB2 PET signal in amyloid-bearing mice due to a lack of significant neuronal loss in this model. However, significant loss of neurons as seen at late stages of AD might decrease the CB2 PET signal due to loss of neuronally-derived CB2. Thus this study in mouse models of AD indicates that a CB2-specific radiotracer can be used as a biomarker of neuroinflammation in the early preclinical stages of AD, when no significant neuronal loss has yet developed.

Recent studies have highlighted a possible role for gut microbiota in modulating Alzheimer's disease pathology, particularly through the actions of gut-derived metabolites and their influence on the immune system. In this issue of the JCI, Chandra et al. reveal that circulating levels of the gut microbiota-derived metabolite propionate affected amyloid burden and glial activation in a mouse model of Aβ amyloidosis. The study also identifies a mechanism for the therapeutic benefit of propionate supplementation, showing that propionate lowered peripheral IL-17 and suppressed Th17 cell activity. These results support the idea of therapeutic targeting of the gut/brain/immune axis, particularly via modulation of Th17 responses, and suggest translational strategies involving microbiome-based or immunological interventions for dementia prevention and treatment.

The KDIGO 2021 guidelines suggest that individuals who test positive for serum anti-phospholipase A2 receptor (anti-PLA2R) antibodies may not require a renal biopsy to establish a diagnosis of membranous nephropathy (MN). However, it is imperative to acknowledge that MN can coexist with other chronic kidney diseases. In instances where MN is comorbid with IgA nephropathy, diabetic nephropathy, or focal segmental glomerulosclerosis, the therapeutic approach tends to be analogous. Nevertheless, there is a significant disparity in both the treatment regimen and the prognosis between MN and renal amyloidosis, with variations existing even among distinct subtypes of renal amyloidosis. Given that both MN and renal amyloidosis exhibit a predilection for the geriatric population, it is prudent to consider the possibility of MN concurrent with renal amyloidosis in elderly patients who test positive for serum anti-PLA2R antibodies. This consideration should precede a straightforward MN treatment strategy. In this report, we present six patients with MN concurrent with renal amyloidosis identified at our center over the past 14 years; in five of whom were positive for serum anti-PLA2R antibodies. We further elucidated the divergent clinicopathological characteristics and prognostic implications of these cases.