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.

Amyloid-Forming Corpora Amylacea and Spheroid-Type Amyloid Deposition: Comprehensive Analysis Using Immunohistochemistry, Proteomics, and a Literature Review.

This study aimed to elucidate the similarities and differences between amyloid-forming corpora amylacea (CA) in the prostate and lung, examine the nature of CAs in cystic tumors of the atrioventricular node (CTAVN), and clarify the distinctions between amyloid-forming CA and spheroid-type amyloid deposition. We conducted proteomics analyses using liquid chromatography-tandem mass spectrometry with laser microdissection and immunohistochemistry to validate the characteristics of CAs in the lung and prostate. Our findings revealed that the CAs in these organs primarily consisted of common proteins (ß2-microglobulin and lysozyme) and locally produced proteins. Moreover, we observed a discrepancy between the histopathological and proteomic analysis results in CTAVN-associated CAs. In addition, while the histopathological appearance of the amyloid-forming CAs and spheroid-type amyloid deposits were nearly identical, the latter deposition lacked ß2-microglobulin and lysozyme and exhibited evident destruction of the surrounding tissue. A literature review further supported these findings. These results suggest that amyloid-forming CAs in the lung and prostate are formed through a shared mechanism, serving as waste containers (wasteosomes) and/or storage for excess proteins (functional amyloids). In contrast, we hypothesize that while amyloid-forming CA and spheroid-type amyloid deposits are formed, in part, through common mechanisms, the latter are pathological.

Corpora amylacea negatively correlate with hippocampal tau pathology in Alzheimer's disease.

Introduction: Severity and distribution of aggregated tau and neurofibrillary tangles (NFT) are strongly correlated with the clinical presentation of Alzheimer's disease (AD). Clearance of aggregated tau could decrease the rate of NFT formation and delay AD onset. Recent studies implicate corpora amylacea (CA) as a regulator of onset or accumulation of tau pathology. Normally, CA clear brain waste products by amassing cellular debris, which are then extruded into the cerebrospinal fluid to be phagocytosed. The proper functioning of CA may slow progression of AD-associated NFT pathology, and this relationship may be influenced by amount and distribution of phospho-tau (pTau) produced, age, sex, and genetic risk. Objective: The goal of this study was to determine if CA size and number are associated with hippocampal location and local pTau severity while accounting for variations in age, sex, and genetic risk. Methods: Postmortem brain hippocampal tissue sections from 40 AD and 38 unaffected donors were immunohistochemically stained with AT8 (pTau) and counter stained with periodic acid Schiff (PAS). Stained sections of the CA1 and CA3 regions of the hippocampus were analyzed. The percent area occupied (%AO) of CA, pTau, and NFT was calculated. Pairwise comparisons and regression modeling were used to analyze the influence of age, pTau %AO, and genetic risk on %AO by CA in each region, separately in donors with AD and unaffected donors. Results: CA %AO was significantly higher in the CA3 region compared to CA1 in both groups. A significant negative correlation of CA %AO with both pTau %AO and neurofibrillary tangle %AO in the CA3 region of AD brain donors was found. Regression analysis in the CA3 region revealed a significant negative association between CA with both pTau and age. Conclusion: We found an increase of CA in the CA3 region, compared to CA1 region, in AD and unaffected donors. This may suggest that the CA3 region is a hub for waste removal. Additionally, the negative correlation between %AO by CA and NFT in the CA3 region of the hippocampus in donors with AD suggests CA could play a role in AD pathologic progression by influencing tau clearance.

Distribution of corpora amylacea in the human midbrain: using synchrotron radiation phase-contrast microtomography, high-field magnetic resonance imaging, and histology.

Corpora amylacea (CA) are polyglucosan aggregated granules that accumulate in the human body throughout aging. In the cerebrum, CA have been found in proximity to ventricular walls, pial surfaces, and blood vessels. However, studies showing their three-dimensional spatial distribution are sparse. In this study, volumetric images of four human brain stems were obtained with MRI and phase-contrast X-ray microtomography, followed up by Periodic acid Schiff stain for validation. CA appeared as hyperintense spheroid structures with diameters up to 30 µm. An automatic pipeline was developed to segment the CA, and the spatial distribution of over 200,000 individual corpora amylacea could be investigated. A threefold-or higher-density of CA was detected in the dorsomedial column of the periaqueductal gray (860-4,200 CA count/mm3) than in the superior colliculus (150-340 CA count/mm3). We estimated that about 2% of the CA were located in the immediate vicinity of the vessels or in the peri-vascular space. While CA in the ependymal lining of the cerebral aqueduct was rare, the sub-pial tissue of the anterior and posterior midbrain contained several CA. In the sample with the highest CA density, quantitative maps obtained with MRI revealed high R2* values and a diamagnetic shift in a region which spatially coincided with the CA dense region.

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.

Polyglucosan body disease in an aged chimpanzee (Pan troglodytes).

A 57-year-old female chimpanzee presented with a brief history of increasing lethargy and rapidly progressive lower-limb weakness that culminated in loss of use. Postmortem examination revealed no significant gross lesions in the nervous system or other organ systems. Histological analysis revealed round, basophilic to amphophilic polyglucosan bodies (PGBs) in the white and gray matter of the cervical, thoracic, lumbar, and coccygeal regions of spinal cord. Only rare PGBs were observed in forebrain samples. The lesions in the spinal cord were polymorphic, and they were positively stained with hematoxylin, periodic acid Schiff, Alcian blue, toluidine blue, Bielschowsky silver, and Grocott-Gomori methenamine-silver methods, and they were negative for von Kossa and Congo Red stains. Immunohistochemical evaluation revealed reactivity with antibodies to ubiquitin, but they were negative for glial fibrillary acidic protein, neuron-specific enolase, neurofilaments, tau protein, and Aß protein. Electron microscopy revealed non-membrane-bound deposits composed of densely packed filaments within axons and in the extracellular space. Intra-axonal PGBs were associated with disruption of the axonal fine structure and disintegration of the surrounding myelin sheath. These findings are the first description of PGBs linked to neurological dysfunction in a chimpanzee. Clinicopathologically, the disorder resembled adult PGB disease in humans.

Thyroid Hormone Transporters MCT8 and OATP1C1 Are Expressed in Pyramidal Neurons and Interneurons in the Adult Motor Cortex of Human and Macaque Brain.

Monocarboxylate transporter 8 (MCT8) and organic anion transporter polypeptide 1C1 (OATP1C1) are thyroid hormone (TH) transmembrane transporters that play an important role in the availability of TH for neural cells, allowing their proper development and function. It is important to define which cortical cellular subpopulations express those transporters to explain why MCT8 and OATP1C1 deficiency in humans leads to dramatic alterations in the motor system. By means of immunohistochemistry and double/multiple labeling immunofluorescence in adult human and monkey motor cortices, we demonstrate the presence of both transporters in long-projection pyramidal neurons and in several types of short-projection GABAergic interneurons in both species, suggesting a critical position of these transporters for modulating the efferent motor system. MCT8 is present at the neurovascular unit, but OATP1C1 is only present in some of the large vessels. Both transporters are expressed in astrocytes. OATP1C1 was unexpectedly found, only in the human motor cortex, inside the Corpora amylacea complexes, aggregates linked to substance evacuation towards the subpial system. On the basis of our findings, we propose an etiopathogenic model that emphasizes these transporters' role in controlling excitatory/inhibitory motor cortex circuits in order to understand some of the severe motor disturbances observed in TH transporter deficiency syndromes.

Abundant copathologies of polyglucosan bodies, frontotemporal lobar degeneration with TDP-43 inclusions and ageing-related tau astrogliopathy in a family with a GBE1 mutation.

AIMS: Adult polyglucosan body disease (APBD) is a progressive neurogenetic disorder caused by 1,4-alpha-glucan branching enzyme 1 (GBE1) mutation with an accumulation of polyglucosan bodies (PBs) in the central and peripheral nervous systems as a pathological hallmark. Here, we report two siblings in a family with a GBE1 mutation with prominent frontotemporal lobar degeneration with TAR DNA-binding protein 43 (FTLD-TDP) and ageing-related tau astrogliopathy (ARTAG) copathologies with PBs in the central nervous system. METHODS: Whole-genome sequencing (WGS) followed by Sanger sequencing (SS) was performed on three affected and two unaffected siblings in a pedigree diagnosed with familial frontotemporal dementia. Out of the affected siblings, autopsies were conducted on two cases, and brain samples were used for biochemical and histological analyses. Brain sections were stained with haematoxylin and eosin and immunostained with antibodies against ubiquitin, tau, amyloid ß, α-synuclein, TDP-43 and fused in sarcoma (FUS). RESULTS: A novel single nucleotide deletion in GBE1, c.1280delG, was identified, which is predicted to result in a reading frameshift, p.Gly427Glufs*9. This variant segregated with disease in the family, is absent from population databases and is predicted to cause loss of function, a known genetic mechanism for APBD. The affected siblings showed a greater than 50% decrease in GBE protein levels. Immunohistochemical analysis revealed widespread FTLD-TDP (type A) and ARTAG pathologies as well as PBs in the brains of two affected siblings for whom an autopsy was performed. CONCLUSIONS: This is the first report of a family with several individuals with a FTD clinical phenotype and underlying copathologies of APBD, FTLD-TDP and ARTAG with a segregating GBE1 loss-of-function mutation in affected siblings. The finding of copathologies of APBD and FTLD-TDP suggests these processes may share a disease mechanism resulting from this GBE1 mutation.

Astrocytes are involved in the formation of corpora amylacea-like structures from neuronal debris in the CA1 region of the rat hippocampus after ischemia.

Recently, we demonstrated that the corpora amylacea (CA), a glycoprotein-rich aggregate frequently found in aged brains, accumulates in the ischemic hippocampus and that osteopontin (OPN) mediates the entire process of CA formation. Therefore, this study aimed to elucidate the mechanisms by which astrocytes and microglia participate in CA formation during the late phase (4-12 weeks) of brain ischemia. Based on various morphological analyses, including immunohistochemistry, in situ hybridization, immunoelectron microscopy, and correlative light and electron microscopy, we propose that astrocytes are the primary cells responsible for CA formation after ischemia. During the subacute phase after ischemia, astrocytes, rather than microglia, express Opn messenger ribonucleic acid and OPN protein, a surrogate marker and key component of CA. Furthermore, the specific localization of OPN in the Golgi complex suggests that it is synthesized and secreted by astrocytes. Astrocytes were in close proximity to type I OPN deposits, which accumulated in the mitochondria of degenerating neurons before fully forming the CA (type III OPN deposits). Throughout CA formation, astrocytes remained closely attached to OPN deposits, with their processes exhibiting well-developed gap junctions. Astrocytic cytoplasmic protein S100ß, a calcium-binding protein, was detected within the fully formed CA. Additionally, ultrastructural analysis revealed direct contact between astroglial fibrils and the forming facets of the CA. Overall, we demonstrated that astrocytes play a central role in mediating CA formation from the initial stages of OPN deposit accumulation to the evolution of fully formed CA following transient ischemia in the hippocampus.

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.

Osteopontin mediates the formation of corpora amylacea-like structures from degenerating neurons in the CA1 region of the rat hippocampus after ischemia.

We previously demonstrated that osteopontin (OPN) is closely associated with calcium precipitation in response to ischemic brain insults. The present study was designed to elucidate the possible association between deposition of OPN and progressive neurodegeneration in the ischemic hippocampus. To address this, we analyzed the OPN deposits in the rat hippocampus after global cerebral ischemia in the chronic phase (4 to 12 weeks) after reperfusion using immunoelectron microscopy and correlative light and electron microscopy. We identified three different types of OPN deposits based on their morphological characteristics, numbered according to the order in which they evolved. Dark degenerative cells that retained cellular morphology were frequently observed in the pyramidal cell layer, and type I OPN deposits were degenerative mitochondria that accumulated among these cells. Type II deposits evolved into more complex amorphous structures with prominent OPN deposits within their periphery and within degenerative mitochondria-like structures. Finally, type III had large concentric laminated structures with irregularly shaped bodies in the center of the deposits. In all types, OPN expression was closely correlated with calcification, as confirmed by calcium fixation and Alizarin Red staining. Notably, type II and III deposits were highly reminiscent of corpora amylacea, glycoprotein-rich aggregates found in aged brains, or neurodegenerative disease, which was further confirmed by ubiquitin expression and periodic acid-Schiff staining. Overall, our data provide a novel link between ongoing neurodegeneration and the formation of corpora amylacea-like structures and calcium deposits in the ischemic hippocampus, suggesting that OPN may play an important role in such processes.

Case report: The origin of transmantle-like features.

The transmantle sign is considered to be a magnetic resonance imaging feature specific to patients with type II focal cortical dysplasia; however, this sign can be difficult to distinguish from other pathologies, such as a radial-oriented white matter band in tuberous sclerosis. Here, we report a case showing a high-intensity area on T2-weighted and fluid-attenuated inversion recovery images extending from the ventricle to the cortex associated with atypical histopathological findings containing corpora amylacea. This case demonstrates that some instances of transmantle signs may be due to corpora amylacea accumulation.

Lipopolysaccharide, Identified Using an Antibody and by PAS Staining, Is Associated With Corpora amylacea and White Matter Injury in Alzheimer's Disease and Aging Brain.

Corpora amylacea (CA) increase in number and size with aging. Their origins and functions remain unknown. Previously, we found that Alzheimer's disease (AD) brains have more CA in the periventricular white matter (PVWM) compared to aging controls. In addition, CA is associated with neurodegeneration as indicated by colocalization of degraded myelin basic protein (dMBP) with periodic acid-Schiff (PAS), a CA marker. We also found that bacterial lipopolysaccharide is present in aging brains, with more LPS in AD compared with controls. Periodic acid-Schiff staining is used to identify CA by virtue of their high polysaccharide content. Despite the growing knowledge of CA as a contributor to AD pathology, the molecules that contribute to the polysaccharides in CA are not known. Notably, lipopolysaccharides (LPS) are important cell-surface polysaccharides found in all Gram-negative bacteria. However, it is unknown whether PAS could detect LPS, whether the LPS found in aging brains contribute to the polysaccharide found in CA, and whether LPS associate with myelin injury. In this study, we found that aging brains had a myelin deficit zone (MDZ) adjacent to the ventricles in PVWM. The MDZ contained vesicles, most of which were CA. LPS and dMBP levels were higher in AD than in control brains. LPS was colocalized with dMBP in the vesicles/CA, linking white matter injury with a bacterial pro-inflammatory molecule. The vesicles also contained oxidized fibers, C-reactive protein, NG2, and GALC, markers of oligodendrocyte precursor cells (OPCs) and oligodendrocyte cells (OLs), respectively. The vesicles/CA were surrounded by dense astrocyte processes in control and AD brains. LPS was co-localized with CA by double staining of PAS with LPS in aging brains. The relationship of LPS with PAS staining was confirmed by PAS staining of purified LPS on nitrocellulose membranes. These findings reveal that LPS is one of the polysaccharides found in CA which can be stained with PAS. In addition, vesicles/CA are associated with oxidized and damaged myelin. The LPS in these vesicles/CA may have contributed to this oxidative myelin damage and may have contributed to oxidative stress to OPCs and OLs which could impair the ability to repair damaged myelin in AD and control brains.

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.

Presence of corpora amylacea among prostate cancer cells: an unrecognised feature of intraductal carcinoma of the prostate.

Corpora amylacea (CA) is usually present in benign prostatic ducts and acini, and its presence is considered suggestive of negative or low-risk prostate cancer. The clinicopathological definition of CA among prostate cancer cells (CAPCCs)-described as CA entirely surrounded by invasive cancer cells-has not been discussed. As intraductal carcinoma of the prostate (IDC-P) is a well-known adverse prognostic factor in prostate cancer, this study aimed to elucidate the relationship between CAPCC and IDC-P. We enrolled 366 patients who underwent robotic-assisted radical prostatectomies between 2012 and 2018 at Aichi Medical University Hospital. All surgical specimens were independently reviewed by two genitourinary pathologists. The median age of the patients was 68.5 years; the median serum prostate-specific antigen was 6.49 ng/mL. IDC-P was observed in 143 (39.1%) patients, while the presence of CAPCC was observed in 47 cases (12.8%). Patients with CAPCC were associated with more advanced clinical and pathological T stages, as well as Gleason scores, than those without CAPCC (p=0.018, p<0.001, p=0.036). Notably, the presence of CAPCC was significantly associated with the presence of IDC-P (39 cases) and a high Gleason score compared with the absence of CAPCC (12 cases) (p<0.001 and p=0.036, respectively). The presence of CAPCC is an adverse pathological feature, often closely related to IDC-P. Therefore, CAPCC may be a surrogate finding to detect IDC-P via haematoxylin and eosin staining.

New insights on fibrodysplasia ossificans progressiva: discussion of an autoptic case report and brief literature review.

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic condition with soft tissue progressive ossification, leading to severe disability. We describe a 27-years-old female affected by FOP who died after a fall. An autopsy was performed. Upper and lower extremities resulted in fixed flexion, with kyphoscoliosis of the spine and chest wall deformity. Moreover, a cranial fracture was pointed out. At histology, atypical abundance of corpora amylacea in gray matter was observed. In a sample of macroscopically non-affected muscular tissue, small areas with necrosis of myocytes and hyperplasia of fibroblasts were seen in light microscopy, with intracellular inorganic dystrophic inclusions in transmission electron microscopy. Thyroid gland histology showed diffuse lymphocytic infiltration. Postmortem examination of FOP patients provided precious information about involvement of other tissues, suggesting an initial and widespread inflammatory/dystrophic phase, to be further investigated, because it might reveal new insights about a FOP mutation cascade.

Expression of reelin with age in the human hippocampal formation.

Reelin plays a key role in neuronal migration and lamination in the cortex and hippocampus. Animal studies have shown that reelin expression decreases with age. The aim of this study was to evaluate the expression of reelin in all layers of the human hippocampal formation across three age groups. We used immunohistochemistry in formalin fixed and paraffin embedded hippocampal tissue from infants (1-10 months; n = 9), children (4-10 years; n = 4), and adults (45-60 years; n = 6) to stain for reelin. Expression was quantified (measured as the number of positive reelin cells/mm2 ) in the granule cell layer of the dentate gyrus (DG), the molecular layer of the dentate gyrus (ML), the hippocampal fissure (HF), stratum lacunosum moleculare (SLM), CA4/Hilus and the stratum pyramidale layer of CA3, CA2, and CA1. Expression of reelin was highest in the HF irrespective of age, followed by the SLM and ML. Minimal to no expression was seen in the stratum pyramidale layer of CA1-3. With age, reelin expression decreased and was statistically significant from infancy to childhood in the HF (p = .02). This study confirms that reelin expression decreases with age in the human hippocampus, and shows for the first time that the major decrease occurs between infancy and early childhood.