Increase in wasteosomes (corpora amylacea) in frontotemporal lobar degeneration with specific detection of tau, TDP-43 and FUS pathology.

Wasteosomes (or corpora amylacea) are polyglucosan bodies that appear in the human brain with aging and in some neurodegenerative diseases, and have been suggested to have a potential role in a nervous system cleaning mechanism. Despite previous studies in several neurodegenerative disorders, their status in frontotemporal lobar degeneration (FTLD) remains unexplored. Our study aims to characterize wasteosomes in the three primary FTLD proteinopathies, assessing frequency, distribution, protein detection, and association with aging or disease duration. Wasteosome scores were obtained in various brain regions from 124 post-mortem diagnosed sporadic FTLD patients, including 75 participants with tau (FTLD-tau), 42 with TAR DNA-binding protein 43 (FTLD-TDP), and 7 with Fused in Sarcoma (FTLD-FUS) proteinopathies, along with 29 control subjects. The wasteosome amount in each brain region for the different FLTD patients was assessed with a permutation test with age at death and sex as covariables, and multiple regressions explored associations with age at death and disease duration. Double immunofluorescence studies examined altered proteins linked to FTLD in wasteosomes. FTLD patients showed a higher accumulation of wasteosomes than control subjects, especially those with FTLD-FUS. Unlike FTLD-TDP and control subjects, wasteosome accumulation did not increase with age in FTLD-tau and FTLD-FUS. Cases with shorter disease duration in FTLD-tau and FTLD-FUS seemed to exhibit higher wasteosome quantities, whereas FTLD-TDP appeared to show an increase with disease progression. Immunofluorescence studies revealed the presence of tau and phosphorylated-TDP-43 in the periphery of isolated wasteosomes in some patients with FTLD-tau and FTLD-TDP, respectively. Central inclusions of FUS were observed in a higher number of wasteosomes in FTLD-FUS patients. These findings suggest a role of wasteosomes in FTLD, especially in the more aggressive forms of FLTD-FUS. Detecting these proteins, particularly FUS, in wasteosomes from cerebrospinal fluid could be a potential biomarker for FTLD.

Analyzing the Virchow pioneering report on brain corpora amylacea: shedding light on recurrent controversies.

The first report of corpora amylacea (CA) is attributed to Morgagni, who described them in the prostate in the eighteenth century. Nearly a hundred years later, and following the lead started by Purkinje, Virchow described them in the brain. He made a detailed description of the most useful techniques to visualize them, but he failed to describe the cause of why CA do appear, why they are mainly linked with the elderly, and which is their clinical significance. Although in the last two centuries CA have received little attention, recent data have been able to describe that CA accumulate waste products and that some of them can be found in the cerebrospinal fluid and lymphatic nodes, after being released from the brain. Indeed, CA have been renamed to wasteosomes to underline the waste products they gather and to avoid confusion with the term amyloid used by Virchow, now widely related to certain protein deposits found in the brain. Here, after providing a commented English translation of Virchow's findings, we provide a recent update on these structures and their connection with the glymphatic system insufficiency, for which wasteosomes should be considered a hallmark, and how these bodies could serve as diagnostic or prognostic markers of various brain conditions.

Uncovering tau in wasteosomes (corpora amylacea) of Alzheimer's disease patients.

Brain corpora amylacea, recently renamed as wasteosomes, are polyglucosan bodies that appear during aging and some neurodegenerative conditions. They collect waste substances and are part of a brain cleaning mechanism. For decades, studies on their composition have produced inconsistent results and the presence of tau protein in them has been controversial. In this work, we reanalyzed the presence of this protein in wasteosomes and we pointed out a methodological problem when immunolabeling. It is well known that to detect tau it is necessary to perform an antigen retrieval. However, in the case of wasteosomes, an excessive antigen retrieval with boiling dissolves their polyglucosan structure, releases the entrapped proteins and, thus, prevents their detection. After performing an adequate pre-treatment, with an intermediate time of boiling, we observed that some brain wasteosomes from patients with Alzheimer's disease (AD) contained tau, while we did not detect tau protein in those from non-AD patients. These observations pointed the different composition of wasteosomes depending on the neuropathological condition and reinforce the role of wasteosomes as waste containers.

Wasteosomes (corpora amylacea) as a hallmark of chronic glymphatic insufficiency.

In different organs and tissues, the lymphatic system serves as a drainage system for interstitial fluid and is useful for removing substances that would otherwise accumulate in the interstitium. In the brain, which lacks lymphatic circulation, the drainage and cleaning function is performed by the glymphatic system, called so for its dependence on glial cells and its similar function to that of the lymphatic system. In the present article, we define glymphatic insufficiency as the inability of the glymphatic system to properly perform the brain cleaning function. Furthermore, we propose that corpora amylacea or wasteosomes, which are protective structures that act as waste containers and accumulate waste products, are, in fact, a manifestation of chronic glymphatic insufficiency. Assuming this premise, we provide an explanation that coherently links the formation, distribution, structure, and function of these bodies in the human brain. Moreover, we open up new perspectives in the study of the glymphatic system since wasteosomes can provide information about which variables have the greatest impact on the glymphatic system and which diseases occur with chronic glymphatic insufficiency. For example, based on the presence of wasteosomes, it seems that aging, sleep disorders, and cerebrovascular pathologies have the highest impact on the glymphatic system, whereas neurodegenerative diseases have a more limited impact. Furthermore, as glymphatic insufficiency is a risk factor for neurodegenerative diseases, information provided by wasteosomes could help to define the strategies and actions that can prevent glymphatic disruptions, thus limiting the risk of developing neurodegenerative diseases.

Wasteosomes (corpora amylacea) of human brain can be phagocytosed and digested by macrophages.

BACKGROUND: Corpora amylacea of human brain, recently renamed as wasteosomes, are granular structures that appear during aging and also accumulate in specific areas of the brain in neurodegenerative conditions. Acting as waste containers, wasteosomes are formed by polyglucosan aggregates that entrap and isolate toxic and waste substances of different origins. They are expelled from the brain to the cerebrospinal fluid (CSF), and can be phagocytosed by macrophages. In the present study, we analyze the phagocytosis of wasteosomes and the mechanisms involved in this process. Accordingly, we purified wasteosomes from post-mortem extracted human CSF and incubated them with THP-1 macrophages. Immunofluorescence staining and time-lapse recording techniques were performed to evaluate the phagocytosis. We also immunostained human hippocampal sections to study possible interactions between wasteosomes and macrophages at central nervous system interfaces. RESULTS: We observed that the wasteosomes obtained from post-mortem extracted CSF are opsonized by MBL and the C3b complement protein. Moreover, we observed that CD206 and CD35 receptors may be involved in the phagocytosis of these wasteosomes by THP-1 macrophages. Once phagocytosed, wasteosomes become degraded and some of the resulting fractions can be exposed on the surface of macrophages and interchanged between different macrophages. However, brain tissue studies show that, in physiological conditions, CD206 but not CD35 receptors may be involved in the phagocytosis of wasteosomes. CONCLUSIONS: The present study indicates that macrophages have the machinery required to process and degrade wasteosomes, and that macrophages can interact in different ways with wasteosomes. In physiological conditions, the main mechanism involve CD206 receptors and M2 macrophages, which trigger the phagocytosis of wasteosomes without inducing inflammatory responses, thus avoiding tissue damage. However, altered wasteosomes like those obtained from post-mortem extracted CSF, which may exhibit waste elements, become opsonized by MBL and C3b, and so CD35 receptors constitute another possible mechanism of phagocytosis, leading in this case to inflammatory responses.

From corpora amylacea to wasteosomes: History and perspectives.

Corpora amylacea (CA) have been described in several human organs and have been associated with ageing and several pathological conditions. Although they were first discovered two centuries ago, their function and significance have not yet been identified. Here, we provide a chronological summary of the findings on CA in various organs and identify their similarities. After collecting and integrating these findings, we propose to consider CA as waste containers created by specific cells, which sequester waste products and foreign products, and assemble them within a glycan structure. The containers are then secreted into the external medium or interstitial spaces, in this latter case subsequently being phagocytosed by macrophages. This proposal explains, among others, why CA are so varied in content, why only some of them contain fibrillary amyloid proteins, why all of them contain glycan structures, why some of them contain neo-epitopes and are phagocytosed, and why they can be intracellular or extracellular structures. Lastly, in order to avoid the ambiguity of the term amyloid (which can indicate starch-like structures but also insoluble fibrillary proteins), we propose renaming CA as "wasteosomes", emphasising the waste products they entrap rather than their misleading amyloid properties.

Corpora Amylacea in the Human Brain Exhibit Neoepitopes of a Carbohydrate Nature.

Corpora amylacea (CA) in the human brain are polyglucosan bodies that accumulate residual substances originated from aging and both neurodegenerative and infectious processes. These structures, which act as waste containers, are released from the brain to the cerebrospinal fluid, reach the cervical lymph nodes via the meningeal lymphatic system and may be phagocytosed by macrophages. Recent studies indicate that CA present certain neoepitopes (NEs) that can be recognized by natural antibodies of the IgM class, and although evidence of different kinds suggests that these NEs may be formed by carbohydrate structures, their precise nature is unknown. Here, we adapted standard techniques to examine this question. We observed that the preadsorption of IgMs with specific carbohydrates has inhibitory effects on the interaction between IgMs and CA, and found that the digestion of CA proteins had no effect on this interaction. These findings point to the carbohydrate nature of the NEs located in CA. Moreover, the present study indicates that, in vitro, the binding between certain natural IgMs and certain epitopes may be disrupted by certain monosaccharides. We wonder, therefore, whether these inhibitions may also occur in vivo. Further studies should now be carried out to assess the possible in vivo effect of glycemia on the reactivity of natural IgMs and, by extension, on natural immunity.

Corpora amylacea act as containers that remove waste products from the brain.

Corpora amylacea (CA) in the human brain are granular bodies formed by polyglucosan aggregates that amass waste products of different origins. They are generated by astrocytes, mainly during aging and neurodegenerative conditions, and are located predominantly in periventricular and subpial regions. This study shows that CA are released from these regions to the cerebrospinal fluid and are present in the cervical lymph nodes, into which cerebrospinal fluid drains through the meningeal lymphatic system. We also show that CA can be phagocytosed by macrophages. We conclude that CA can act as containers that remove waste products from the brain and may be involved in a mechanism that cleans the brain. Moreover, we postulate that CA may contribute in some autoimmune brain diseases, exporting brain substances that interact with the immune system, and hypothesize that CA may contain brain markers that may aid in the diagnosis of certain brain diseases.

[Nutritional and functional state of patients with chronic obstructive pulmonary disease: effects of oral nutritional supplementation (OFOS study)]. / Estado nutricional y funcional en pacientes con enfermedad pulmonar obstructiva crónica: efectos de la suplementación nutricional oral (estudio OFOS).

INTRODUCTION: Weight loss and malnutrition are associated with a worse prognosis of chronic obstructive pulmonary disease (COPD). OBJECTIVE: The main objective of the OFOS study was to assess the efficacy and tolerability of a new nutritional oral formula in adults with COPD with weight loss or malnutrition. METHODS: Prospective, single-centre, randomized, open-label and controlled trial conducted in Lima (Peru). A total of 99 outpatients of both sexes were included (control [GC]: 49; supplement [GS]: 50), aged from 18 to 80 years old, who had been diagnosed with COPD and that suffered from malnutrition or involuntary weight loss during the last months. Nutritional, functional and quality of life (QoL) variables were evaluated during a three-month intervention. RESULTS: At three months, there was an increase of body mass index (BMI) and fat free mass index (FFMI) significantly higher in the GS: IMC 5.3% vs 2.9%, p < 0.001; FFMI 3.2% vs 1.9%, p = 0.019. The GS showed a reduction of cases with BMI < 21 kg/m2 equivalent to 69% vs33% in the GC (p = 0.004). Functional variables showed a favourable improvement trend in GS, being significant for the hand-grip test in the subgroup of patients with low FFMI (p = 0.001). All QoL studied variables significantly improved in both groups (p < 0.001). CONCLUSIONS: Oral supplementation with a complete, polymeric and normocaloric new nutritional formula for three months was well tolerated and effective for the nutritional support of patients diagnosed with COPD with weight loss or malnutrition.

INTRODUCCIÓN: la pérdida de peso y la desnutrición se asocian a un peor pronóstico de la enfermedad pulmonar obstructiva crónica (EPOC).OBJETIVO: el objetivo del estudio OFOS fue valorar la eficacia y tolerabilidad de una nueva fórmula nutricional oral en adultos con EPOC con pérdida de peso o desnutrición. MÉTODOS: estudio prospectivo, unicéntrico, aleatorizado, abierto y controlado realizado en Lima (Perú). Se incluyeron 99 pacientes ambulatorios de ambos sexos (control [GC]: 49; suplemento [GS]: 50), entre 18 y 80 años con diagnóstico de EPOC y con pérdida involuntaria de peso en los últimos meses o desnutrición. Se evaluaron variables nutricionales, funcionales y de calidad de vida (CV) durante un periodo de intervención de tres meses. RESULTADOS: a los tres meses, hubo un incremento del índice de masa corporal (IMC) y del índice de masa libre de grasa (IMLG) significativamente superior en el GS: IMC: 5,3% vs.2,9%, p < 0,001; IMLG: 3,2% vs.1,9%, p = 0,019. El GS mostró una reducción de casos con IMC < 21 kg/m2 equivalente al 69% vs.33% en el GC (p = 0,004). Las variables funcionales mostraron una tendencia a la mejoría favorable al GS, siendo significativa para la fuerza de la mano (hand-grip test)en el subgrupo de pacientes con IMLG bajo (p = 0,001). Todas las variables estudiadas de CV mejoraron significativamente en ambos grupos (p < 0,001). CONCLUSIONES: la suplementación oral durante tres meses con una nueva fórmula completa, polimérica y normocalórica fue bien tolerada y eficaz para el soporte nutricional de pacientes diagnosticados de EPOC con pérdida de peso o desnutrición.

Estado nutricional y funcional en pacientes con enfermedad pulmonar obstructiva crónica: efectos de la suplementación nutricional oral (estudio OFOS) / Nutritional and functional state of patients with chronic obstructive pulmonary disease: effects of oral nutritional supplementation (OFOS study)

Introducción: la pérdida de peso y la desnutrición se asocian a un peor pronóstico de la enfermedad pulmonar obstructiva crónica (EPOC). Objetivo: el objetivo del estudio OFOS fue valorar la eficacia y tolerabilidad de una nueva fórmula nutricional oral en adultos con EPOC con pérdida de peso o desnutrición. Métodos: estudio prospectivo, unicéntrico, aleatorizado, abierto y controlado realizado en Lima (Perú). Se incluyeron 99 pacientes ambulatorios de ambos sexos (control [GC]: 49; suplemento [GS]: 50), entre 18 y 80 años con diagnóstico de EPOC y con pérdida involuntaria de peso en los últimos meses o desnutrición. Se evaluaron variables nutricionales, funcionales y de calidad de vida (CV) durante un periodo de intervención de tres meses. Resultados: a los tres meses, hubo un incremento del índice de masa corporal (IMC) y del índice de masa libre de grasa (IMLG) significativamente superior en el GS: IMC: 5,3% vs. 2,9%, p < 0,001; IMLG: 3,2% vs. 1,9%, p = 0,019. El GS mostró una reducción de casos con IMC < 21 kg/ m2 equivalente al 69% vs. 33% en el GC (p = 0,004). Las variables funcionales mostraron una tendencia a la mejoría favorable al GS, siendo significativa para la fuerza de la mano (hand-grip test) en el subgrupo de pacientes con IMLG bajo (p = 0,001). Todas las variables estudiadas de CV mejoraron significativamente en ambos grupos (p < 0,001). Conclusiones: la suplementación oral durante tres meses con una nueva fórmula completa, polimérica y normocalórica fue bien tolerada y eficaz para el soporte nutricional de pacientes diagnosticados de EPOC con pérdida de peso o desnutrición (AU)

Introduction: Weight loss and malnutrition are associated with a worse prognosis of chronic obstructive pulmonary disease (COPD). Objective: The main objective of the OFOS study was to assess the efficacy and tolerability of a new nutritional oral formula in adults with COPD with weight loss or malnutrition. Methods: Prospective, single-centre, randomized, open-label and controlled trial conducted in Lima (Peru). A total of 99 outpatients of both sexes were included (control [GC]: 49; supplement [GS]: 50), aged from 18 to 80 years old, who had been diagnosed with COPD and that suffered from malnutrition or involuntary weight loss during the last months. Nutritional, functional and quality of life (QoL) variables were evaluated during a three-month intervention. Results: At three months, there was an increase of body mass index (BMI) and fat free mass index (FFMI) significantly higher in the GS: IMC 5.3% vs 2.9%, p < 0.001; FFMI 3.2% vs 1.9%, p = 0.019. The GS showed a reduction of cases with BMI < 21 kg/m2 equivalent to 69% vs 33% in the GC (p = 0.004). Functional variables showed a favourable improvement trend in GS, being significant for the hand-grip test in the subgroup of patients with low FFMI (p = 0.001). All QoL studied variables significantly improved in both groups (p < 0.001. Conclusions: Oral supplementation with a complete, polymeric and normocaloric new nutritional formula for three months was well tolerated and effective for the nutritional support of patients diagnosed with COPD with weight loss or malnutrition (AU)