Validating novel tau positron emission tomography tracer [F-18]-AV-1451 (T807) on postmortem brain tissue.

OBJECTIVE: To examine region- and substrate-specific autoradiographic and in vitro binding patterns of positron emission tomography tracer [F-18]-AV-1451 (previously known as T807), tailored to allow in vivo detection of paired helical filament-tau-containing lesions, and to determine whether there is off-target binding to other amyloid/non-amyloid proteins. METHODS: We applied [F-18]-AV-1451 phosphor screen autoradiography, [F-18]-AV-1451 nuclear emulsion autoradiography, and [H-3]-AV-1451 in vitro binding assays to the study of postmortem samples from patients with a definite pathological diagnosis of Alzheimer disease, frontotemporal lobar degeneration-tau, frontotemporal lobar degeneration-transactive response DNA binding protein 43 (TDP-43), progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies, multiple system atrophy, cerebral amyloid angiopathy and elderly controls free of pathology. RESULTS: Our data suggest that [F-18]-AV-1451 strongly binds to tau lesions primarily made of paired helical filaments in Alzheimer brains (eg, intraneuronal and extraneuronal tangles and dystrophic neurites), but does not seem to bind to a significant extent to neuronal and glial inclusions mainly composed of straight tau filaments in non-Alzheimer tauopathy brains or to lesions containing ß-amyloid, α-synuclein, or TDP-43. [F-18]-AV-1451 off-target binding to neuromelanin- and melanin-containing cells and, to a lesser extent, to brain hemorrhagic lesions was identified. INTERPRETATION: Our data suggest that [F-18]-AV-1451 holds promise as a surrogate marker for the detection of brain tau pathology in the form of tangles and paired helical filament-tau-containing neurites in Alzheimer brains but also point to its relatively lower affinity for lesions primarily made of straight tau filaments in non-Alzheimer tauopathy cases and to the existence of some [F-18]-AV-1451 off-target binding. These findings provide important insights for interpreting in vivo patterns of [F-18]-AV-1451 retention.

Characterization of cytoplasmic hyaline bodies in a hepatocellular carcinoma of a dog.

This report describes the morphological and immunohistochemical features of intracytoplasmic inclusion bodies found in a 13-year-old Yorkshire dog with a hepatocellular carcinoma and referred for anorexia, lethargy and mild polydipsia. Fine-needle aspirates of the large abdominal mass revealed high number of pleomorphic neoplastic hepatocytes, containing round to polygonal, well-demarcated, hyaline bodies. Same findings were histologically confirmed on multiple biopsies. Immunohistochemically, the inclusion bodies were negative for alpha-1-antitrypsin, carcinoembryonary antigen, fibrinogen, IgG, IgM, cytokeratins 7, 8, 18, 19, 20. By transmission electron microscopy, the cytoplasmic inclusions were composed of granular homogeneous or reticulated electrondense matrix, enclosed within dilated rough endoplasmic reticulum or remnants of its membranes, consistent with proteinaceous material accumulated within neoplastic hepatocytes due to aberrant protein secretion or transport. This is the first detailed characterization of hyaline cytoplasmic inclusion bodies in canine hepatocellular carcinoma.

Microvillus inclusion disease: prenatal ultrasound findings, molecular diagnosis and genetic counseling of congenital diarrhea.

OBJECTIVE: To present prenatal ultrasound findings and molecular diagnosis of microvillus inclusion disease, and to review the literature of abnormal prenatal ultrasound findings associated with congenital diarrhea. MATERIALS, METHODS AND RESULTS: A 21-year-old woman, gravida 1, para 0, had generalized bowel dilation of the fetus on prenatal ultrasound at 29 gestational weeks. She and her husband were non-consanguineous, and there was no family history of congenital diarrhea. Prenatal ultrasound at 29 gestational weeks revealed a honeycomb appearance of the bowel without ascites or intraperitoneal calcification. At 36 gestational weeks, polyhydramnios dilated bowel loops were observed, and a 3,355-g male baby was delivered with a distended abdomen. Postnatally, the neonate suffered from watery diarrhea and abdominal distension but there was no mechanical bowel obstruction. An endoscopic biopsy of the small bowel revealed intracytoplasmic inclusions lined by intact microvilli in the apical surface of the intestinal epithelial cells consistent with the diagnosis of microvillus inclusion disease. Mutation analysis of blood samples of the neonate and parents revealed a heterozygous nonsense mutation of c.445C

Survival impact of psammoma body, stromal calcification, and bone formation in papillary thyroid carcinoma.

The presence of calcification is the most significant ultrasonographic finding in evaluating thyroid nodules. Calcifications are more frequently detected in papillary thyroid carcinoma than in other thyroid lesions. However, the clinical significance of calcification, including clinical correlations and impact on survival, and the molecular mechanism responsible for calcification in papillary thyroid carcinoma remain uncertain. We performed a retrospective study of patients with primary common-type papillary thyroid carcinoma to determine the clinical correlations of calcification and its impact on survival. Histologically, calcification was classified as either psammoma bodies, stromal calcification, or bone formation. They were identified in 25, 47, and 13% of all 229 cases of papillary thyroid carcinoma, respectively. The presence of psammoma bodies was significantly correlated with gross lymph node metastasis and stage grouping. Both stromal calcification and bone formation were significantly correlated with patient age. In addition, stromal calcification was associated with pT classification and gross lymph node metastasis. Papillary thyroid carcinoma with, compared to that without, psammoma bodies was associated with poorer disease-free survival. We examined the quantitative expression of BMP-1, a metalloproteinase that is reported to be involved in bone and extracellular matrix formations, and found that its expression was significantly higher in tumors with psammoma bodies or with stromal calcification (P=0.0464 and 0.0272, respectively). These results suggest that the presence of psammoma bodies is a useful predictor of outcome for patients suffering from papillary thyroid carcinoma.

Pilot study for in vivo cellular imaging of the muscularis propria and ex vivo molecular imaging of myenteric neurons (with video).

BACKGROUND: It is challenging to optimally sample the muscularis propria endoscopically for the diagnosis of muscle layer diseases, especially for motility disorders resulting from neuroenteric dysfunction. OBJECTIVES: Ultramagnification in vivo imaging of the muscularis mucosa and ex vivo identification of myenteric neuronal elements by confocal microscopy. DESIGN: Ex vivo and in vivo porcine animal studies. SETTING: Short-term study in an animal laboratory. INTERVENTIONS: The muscularis propria in the stomach and esophagus was accessed by resecting the mucosal layer with endoscopic submucosal dissection or cap EMR techniques or by creating a submucosal space by the submucosal endoscopy with mucosal flap technique. The muscularis propria was stained with Nissl stains and 2 types of neuronal molecular stains. The muscular layer was imaged with the endocytoscope in vivo. The muscularis stained with molecular-based stains was also evaluated with a confocal microscope. RESULTS: Cellular microstructures resembling spindle-shaped smooth muscle cells were visualized by endocytoscopy in vivo. Confocal endoscopic microscopy demonstrated that in vivo topical application of neuronal molecular stains successfully stained the muscularis and specifically highlighted neuron-like cells. LIMITATION: Animal model pilot study. CONCLUSIONS: In vivo endoscopic histologic evaluation of the muscularis propria is technically feasible and easy. Minimally invasive advanced endoscopic imaging may be useful for the diagnosis and study of neuroenteric disorders at the level of the muscularis propria, avoiding surgical full-thickness tissue sampling.

[IgG-kappa type multiple myeloma with cytoplasmic crystalline inclusions].

An 82-year-old male was admitted to our hospital because of anemia with Hb 6.9/dl. The serum monoclonal IgG of the kappa type was detected. Bone marrow aspiration showed the presence of 38.9% atypical plasma cells with crystalline inclusions. These crystalline inclusions were stained with acid phosphatase, and remained unstained with MPO, PAS and Congo-Red staining. Immunofluorescence studies showed the plasma cells were positive for IgG-kappa type immunoglobulin and CD138. Electron microscopy revealed varying numbers of stick-like, rod-shaped, rhomboid or rectangular crystals of a variety of lengths and sizes with a periodicity giving an appearance of longitudinal striation. The inclusions were most often surrounded by ribosomes. Some crystalline inclusions were located in the rough-surfaced endoplasmic reticulum. Their presence was probably due to an abnormality in the synthesis and/or secretion of immunoglobulin.

Ultrastructural localization of intraneuronal Abeta-peptide in Alzheimer disease brains.

Autopsied brain tissue from Alzheimer's disease patients and old non-demented controls was studied after immunocytochemistry with the 4G8 monoclonal antibody that recognizes amyloid-beta peptides. Intraneuronal 4G8-positive reaction product was detected in all of the studied brains. The same brain regions in the Alzheimer's disease samples consistently showed both more immunopositive neurons and more stained reaction product per neuron than those from the non-demented brains. Ultrastructurally, the immunopositive reaction product accumulated in clusters of cytoplasmic elements that had a lipofuscin-like appearance, showed a fibrogranular content and were also closely apposed to lipid droplets located either on their periphery or within them. The most strongly 4G8-immunopositive elements had diffuse limits with their fibrogranular content free in the cytoplasm, whereas elements either without or showing only light immunoreaction had a limiting membrane. All immunopositive neurons displayed a similar pattern of clumping heterochromatin. The hypothetical neurotoxic role of intraneuronal amyloid-beta peptides free in the cytoplasm is discussed as is the possible relationship between the amyloid-beta peptides recognized by the 4G8 antibody and the lipid droplets which would presumably contain esterified cholesterol.

Noninclusion-body infantile digital fibromatosis: a lesion heralding terminal osseous dysplasia and pigmentary defects syndrome.

This report describes the histologic and immunohistochemical features of a peculiar type of digital fibroma that shares some clinical and microscopic features with the more common inclusion-body type infantile digital fibromatosis. However, this type does not exhibit inclusion bodies and its cells are reactive for vimentin but not for actin. Significantly, it presents in combination with a constellation of other clinical findings, i.e., mainly positional and bone abnormalities of the fingers and toes, and skin pigmentary defects. Thus, noninclusion-body digital fibromatosis may represent the first clue for the diagnosis of the so-called terminal osseous dysplasia and pigmentary defects syndrome.

A novel tau mutation, S320F, causes a tauopathy with inclusions similar to those in Pick's disease.

Mutations in the tau gene cause familial frontotemporal dementia and parkinsonism linked to chromosome 17. In this article, we describe a novel missense mutation, S320F, in the tau gene in a family with presenile dementia. To our knowledge, it is the first mutation to be described in exon 11 of tau. The proband died at age 53 years, after a disease duration of 15 years, and autopsy revealed a neuropathological picture similar to Pick's disease. Recombinant tau protein with the S320F mutation showed a greatly reduced ability to promote microtubule assembly.

Microvillus inclusion disease as a cause of severe protracted diarrhea in infants.

There are many etiologies responsible for severe intractable diarrhea in infancy, for instance, autoimmune enteropathy, microvillus inclusion disease, tufting enteropathy, food allergy, post-enteritis syndrome, chronic intestinal pseudo-obstruction, Hirschsprung's disease, intestinal lymphangiectasia, congenital sodium or chloride diarrhea, and congenital enzymatic deficiency. This article reports a case of microvillus inclusion disease in a Thai patient. He presented with severe intractable watery diarrhea with persistent metabolic acidosis. After extensive investigation, the diagnosis of microvillus inclusion disease was made, based on the ultrastructural findings of microvillus inclusions in the cytoplasm of the enterocyte on electron microscopic study. Various treatments were introduced to the patient without clinical improvement, including cholestyramine, metronidazole, probiotics, and octreotide. He was dependent on total parenteral nutrition and subsequently died from TPN-related complications. Even though it is a rare disease, it should be considered if an infant has chronic secretory diarrhea.

Nemaline myopathy: two autopsy reports.

Nemaline myopathy belongs to the group of congenital non-progressive myopathies; however, in rare cases death occurs in early infancy. We report two cases of rapidly fatal nemaline myopathy. The first patient, who died at the age of 26 months, showed atrophy of type 1 fibers containing numerous rods in biopsy sections. Biopsy of the second patient, who had died at the age of 5 months, revealed severe maturational arrest and myopathy, but rods were so rare that diagnosis could only be made at the ultrastructural level. Autopsy of both patients showed that atrophy of type 1 fibers and maturational arrest had disappeared in the very same muscles; rods had moved to a central position in the first and significantly increased in number in the second case. Diaphragma muscles contained abundant amounts of rods in both cases. The cardiac musculature showed a few rods only in the first patient, who had developed heart insufficiency 11 months prior to death. Immunohistochemical analysis showed that rods did not contain desmin or ubiquitin.

Inclusion body myositis as a cause of respiratory failure.

Inclusion body myositis (IBM) is a slowly progressive myopathy that has not been reported to affect respiratory muscles. It is often refractory to treatment and a muscle biopsy specimen is necessary for the diagnosis. This is a report of a patient with IBM who quickly progressed to respiratory muscle failure requiring intubation.