Absence Of Amyloid Research Articles

Primary age-related tauopathy (PART): a common pathology associated with human aging.

We recommend a new term, "primary age-related tauopathy" (PART), to describe a pathology that is commonly observed in the brains of aged individuals. Many autopsy studies have reported brains with neurofibrillary tangles (NFTs) that are indistinguishable from those of Alzheimer's disease (AD), in the absence of amyloid (Aβ) plaques. For these "NFT+/Aβ-" brains, for which formal criteria for AD neuropathologic changes are not met, the NFTs are mostly restricted to structures in the medial temporal lobe, basal forebrain, brainstem, and olfactory areas (bulb and cortex). Symptoms in persons with PART usually range from normal to amnestic cognitive changes, with only a minority exhibiting profound impairment. Because cognitive impairment is often mild, existing clinicopathologic designations, such as "tangle-only dementia" and "tangle-predominant senile dementia", are imprecise and not appropriate for most subjects. PART is almost universally detectable at autopsy among elderly individuals, yet this pathological process cannot be specifically identified pre-mortem at the present time. Improved biomarkers and tau imaging may enable diagnosis of PART in clinical settings in the future. Indeed, recent studies have identified a common biomarker profile consisting of temporal lobe atrophy and tauopathy without evidence of Aβ accumulation. For both researchers and clinicians, a revised nomenclature will raise awareness of this extremely common pathologic change while providing a conceptual foundation for future studies. Prior reports that have elucidated features of the pathologic entity we refer to as PART are discussed, and working neuropathological diagnostic criteria are proposed.

Absence of amyloid β oligomers at the postsynapse and regulated synaptic Zn2+ in cognitively intact aged individuals with Alzheimer's disease neuropathology.

BackgroundEarly cognitive impairment in Alzheimer Disease (AD) is thought to result from the dysfunctional effect of amyloid beta (Aβ) oligomers targeting the synapses. Some individuals, however, escape cognitive decline despite the presence of the neuropathologic features of AD (Aβ plaques and neurofibrillary tangles). We term this group Non-Demented with AD Neuropathology or NDAN. The present study illustrates one putative resistance mechanism involved in NDAN cases which may suggest targets for the effective treatment of AD.ResultsHere we describe the localization of Aβ oligomers at the postsynapse in hippocampi from AD cases. Notably, however, we also found that while present in soluble fractions, Aβ oligomers are absent from hippocampal postsynapses in NDAN cases. In addition, levels of phosphorylated (active) CREB, a transcription factor important for synaptic plasticity, are normal in NDAN individuals, suggesting that their synapses are functionally intact. Analysis of Zn2+ showed that levels were increased in both soluble fractions and synaptic vesicles in AD hippocampi, paralleled by a decrease of expression of the synaptic vesicle Zn2+ transporter, ZnT3. Conversely, in NDAN individuals, levels of Zn2+ in soluble fractions were significantly lower than in AD, whereas in synaptic vesicles the levels of Zn2+ were similar to AD, but accompanied by preserved expression of the ZnT3.ConclusionsTaken together, these data illustrate that despite substantial AD neuropathology, Aβ oligomers, and increased synaptic vesicle Zn2+, susceptible brain tissue in these aged NDAN individuals features, as compared to symptomatic AD subjects, significantly lower total Zn2+ levels and no association of Aβ oligomers with the postsynapse, which collectively may promote the maintenance of intact cognitive function.

Association Between In Vivo Fluorine 18–Labeled Flutemetamol Amyloid Positron Emission Tomography Imaging and In Vivo Cerebral Cortical Histopathology

To determine the correspondence of in vivo quantitative estimates of brain uptake of fluorine 18-labeled flutemetamol with immunohistochemical estimates of amyloid levels in patients who underwent previous biopsy. Cross-sectional study of ¹⁸F-flutemetamol positron emission tomography (PET) findings in patients with prior cortical biopsy specimen stained for the presence or absence of amyloid plaques. University hospital. Patients Seven patients who previously had a prior right frontal cortical biopsy at the site of ventriculoperitoneal placement for presumed normal pressure hydrocephalus were recruited. Inclusion criteria included an adequate biopsy specimen for detection and quantification of β-amyloid pathology and age older than 50 years. Intervention All patients underwent an ¹⁸F-flutemetamol PET scan. Quantitative measures of ¹⁸F-flutemetamol uptake (standardized uptake value ratio, a ratio of mean target cortex activity divided by that in a cerebellar reference region) were made at a location contralateral to the biopsy site and compared with estimates of amyloid load based on immunohistochemical and histological staining. There was complete agreement between visual reads of ¹⁸F-flutemetamol PET scans (3 blinded readers with majority rule) and histology. A regression model, including time from biopsy as a covariate, demonstrated a significant relationship (P = .01) between ¹⁸F-flutemetamol uptake and percentage of area of amyloid measured by a monoclonal antibody raised against amyloid (NAB228). Similar results were found with the amyloid-specific monoclonal antibody 4G8 and Thioflavin S. To our knowledge, these data are the first to demonstrate the concordance of ¹⁸F-flutemetamol PET imaging with histopathology, supporting its sensitivity to detect amyloid and potential use in the study and detection of Alzheimer disease.

Amyloid and glucose imaging in dementia with Lewy bodies and multiple systems atrophy

Background Multiple Systems Atrophy (MSA) and Dementia with Lewy bodies (DLB) can present with both REM behavior disorder and severe autonomic dysfunction. In rare occasions, patients with MSA progress to cognitive impairment and even dementia. Positron emission topography (PET) imaging using both the amyloid ligand Pittsburgh Compound B (11C-PiB) and 18 flurodeoxyglucose (18F-FDG) was used to ascertain the presence of amyloid and pattern of glucose metabolic derangement in both disorders. Methods Patients diagnosed with probable DLB or MSA, with clinical symptoms of either REM Behavior Disorder (RBD), Parkinsonism, or dysautonomia were prospectively identified. All underwent both 11C-PiB and 18F-FDG PET imaging. Statistical comparison between DLB, MSA, and normal controls was performed. Results Six patients, 3 with DLB, 2 with Parkinson predominant MSA (MSA-P), and 1 with cerebellar predominant MSA (MSA-C) were identified. Increased level of PiB retention was noted in all patients diagnosed with DLB, but was absent in MSA. In those with DLB, glucose hypometabolism corresponded with regions of amyloid presence, and included prefrontal, parietotemporal, occipital and primary visual cortex regions. MSA patients were distinguished by cerebellar glucose hypometabolism. Conclusions These findings emphasize the distinguishing characteristics between the alpha-synuclein related disorders of DLB and MSA. The absence of amyloid in the cases of MSA is a possible distinguishing characteristic of the disorder.

Tau, prions and Aβ: the triad of neurodegeneration.

This article highlights the features that connect prion diseases with other cerebral amyloidoses and how these relate to neurodegeneration, with focus on tau phosphorylation. It also discusses similarities between prion disease and Alzheimer’s disease: mechanisms of amyloid formation, neurotoxicity, pathways involved in triggering tau phosphorylation, links to cell cycle pathways and neuronal apoptosis. We review previous evidence of prion diseases triggering hyperphosphorylation of tau, and complement these findings with cases from our collection of genetic, sporadic and transmitted forms of prion diseases. This includes the novel finding that tau phosphorylation consistently occurs in sporadic CJD, in the absence of amyloid plaques.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-010-0691-0) contains supplementary material, which is available to authorized users.

Sulfated Polysaccharides Promote the Assembly of Amyloid β1–42 Peptide into Stable Fibrils of Reduced Cytotoxicity

The histopathological hallmarks of Alzheimer disease are the self-aggregation of the amyloid beta peptide (Abeta) in extracellular amyloid fibrils and the formation of intraneuronal Tau filaments, but a convincing mechanism connecting both processes has yet to be provided. Here we show that the endogenous polysaccharide chondroitin sulfate B (CSB) promotes the formation of fibrillar structures of the 42-residue fragment, Abeta(1-42). Atomic force microscopy visualization, thioflavin T fluorescence, CD measurements, and cell viability assays indicate that CSB-induced fibrils are highly stable entities with abundant beta-sheet structure that have little toxicity for neuroblastoma cells. We propose a wedged cylinder model for Abeta(1-42) fibrils that is consistent with the majority of available data, it is an energetically favorable assembly that minimizes the exposure of hydrophobic areas, and it explains why fibrils do not grow in thickness. Fluorescence measurements of the effect of different Abeta(1-42) species on Ca(2+) homeostasis show that weakly structured nodular fibrils, but not CSB-induced smooth fibrils, trigger a rise in cytosolic Ca(2+) that depends on the presence of both extracellular and intracellular stocks. In vitro assays indicate that such transient, local Ca(2+) increases can have a direct effect in promoting the formation of Tau filaments similar to those isolated from Alzheimer disease brains.

Seminal vesicle amyloidosis does not provide any protection from invasion by prostate cancer

To determine whether seminal vesicle amyloidosis (SVA, an unusual finding in prostatectomy specimens, with deposits usually localized and asymptomatic) affects the extension of prostate cancer into the SVs. We identified 73 cases of localized SVA from 6575 prostatectomy specimens, that were removed because of clinically localized prostate cancer. All cases were confirmed by Congo red staining and polarization microscopy. The mean thickness of the amyloid band was measured in each case and correlated with clinicopathological characteristics. The frequency of SV involvement by prostate cancer in the presence of amyloid was compared with the percentage of pT3b classifications in the absence of amyloid. The mean (range) age of the patients with localized SVAs was 64.4 (52-73) years. The mean thickness of the amyloid band did not correlate with patient age, preoperative prostate-specific antigen levels, the weight of the prostates, or the Gleason score and T category of the prostate cancers. In the SVA group, seven cancers invaded the SVs (9.6%), which was not significantly different from the percentage of SV involvement by cancer in total sample (9.2%, P = 0.932). The pathogenesis of localized SVA remains poorly understood, but SVA does not seem to provide an absolute or relative protection from SV involvement by prostate cancer.

X‐linked Emery–Dreifuss muscular dystrophy and vacuoles: An immunohistochemical characterization

We report a striking abundance of rimmed vacuoles in two brothers with X-linked Emery-Dreifuss muscular dystrophy (X-EDMD) confirmed by the absence of emerin at the muscular nuclear envelope and by genetic analysis showing a new 2-bp deletion in exon 6 of the STA gene at the Xq28 region. Immunohistochemical analysis of the vacuoles revealed expression of dystrophin but not of merosin in the sarcolemma of rimmed vacuoles and absence of amyloid and membrane attack complex (MAC) deposition either in vacuoles or muscle fibers. The presence of rimmed vacuoles can be a histopathological finding in X-EDMD, and the diagnosis should not be excluded in clinically well-defined EDMD patients because of this finding.

Amyloidosis: Recognition, Confirmation, Prognosis, and Therapy

Amyloidosis: Recognition, Confirmation, Prognosis, and Therapy

Proteic composition of corpora amylacea in the bovine mammary gland

Histochemical studies of mammary gland sections obtained from healthy lactating Prim'Holstein cows contained numerous corpora amylacea, mainly located in active alveoli. Observations by electron microscopy revealed a cauliflower shape, with a fibrillar or multilayered organization. Mineral studies confirmed the presence of high calcium levels (12.3% of dry matter) and phosphorus (7.4%) in the corpora amylacea composition. These bodies stained positive to Von Kossa silver nitrate and to Periodic acid-Schiff. However, depending on the gland of origin, corpora amylacea stained positive or negative to Congo red. Histochemical studies seemed, therefore, insufficient to determine the presence or absence of amyloid. The amount of total protein varied by approximately 25%. Immunoblotting and analysis of the amino acid sequence of a peptidic fragment obtained from corpora amylacea gave clear evidence of the occurrence of caseins, β-lactoglobulin and α-lactalbumin. However, the comparison between the amino acid composition of corpora amylacea and those of the main milk proteins indicated the presence of other proteins. Electrophoretic analysis also gave evidence of the presence of several other proteins, i.e. glycoproteins. Therefore, it is probable that corpora amylacea composition is much more complex than previously reported.

Immune reactions associated with cerebral amyloid angiopathy.

Cerebral amyloid angiopathy (CAA) occasionally coexists with cerebral vasculitis. An immune system may influence deposition or degradation of the amyloid in cerebral blood vessels. The purpose of this study was to elucidate immune reactions associated with CAA. In 11 elderly patients with sporadic CAA, 2 patients with Icelandic familial CAA, and 2 patients with CAA and granulomatous angiitis, the cerebrovascular amyloid proteins and infiltrating inflammatory cells were analyzed immunohistochemically. In both sporadic CAA (beta-protein amyloid angiopathy) and Icelandic familial CAA (cystatin C amyloid angiopathy), leptomeningeal and cortical vessels were associated with an increase or activation of monocyte/macrophage lineage cells. In the cases of CAA with granulomatous angiitis, the vascular amyloid was of beta-protein and associated with infiltration of many monocyte/macrophage lineage cells, which included multinucleated giant cells containing the amyloid in the cytoplasm as well as T cells composed of CD4+ and CD8+ subsets. Amyloid P component, which was reported to be a common component of amyloid deposits and to prevent phagocytic proteolysis of amyloid fibrils of beta-protein, was negative for the vascular amyloid in a case of CAA with granulomatous angiitis but positive in the others. In both the beta-protein and cystatin C amyloid angiopathies, cerebrovascular amyloid deposition was associated with an increase or activation of monocyte/macrophage lineage cells. Prominent reactions of monocyte/macrophage lineage cells admixed with CD4+ and CD8+ T cells (granulomatous angiitis) were occasionally associated with beta-protein angiopathy. In some of these cases, the absence of amyloid P component might be related to pathogenesis of the granulomatous reaction.

Absence of amyloid from transplanted liver in Met-30 TTR FAP: Evidence from post-mortem specimens

Absence of amyloid from transplanted liver in Met-30 TTR FAP: Evidence from post-mortem specimens

Monoclonal Immunoglobulin Deposition Disease: Light Chain and Light and Heavy Chain Deposition Diseases and Their Relation to Light Chain Amyloidosis

Monoclonal immunoglobulin deposition occurs in tissues as Congo Red binding fibrils in light chain amyloidosis, as less structured deposits in light chain deposition disease, and as similar but distinct deposits in light and heavy chain deposition disease. The nonamyloid forms were found in 13 patients who had evidence of plasmacytic dyscrasia by the immunohistochemical detection of immunoglobulin light chains of kappa or lambda class (with or without staining for a single heavy chain isotype) and by the absence of amyloid P component in tissue sections that did not show the birefringence characteristic of amyloid after Congo Red staining. All but two of the patients presented with proteinuria with or without azotemia. Clinical syndromes involving other organ systems were less common but occasionally severe. Four patients had overt multiple myeloma. Three others had hypercalcemia and mild bone marrow plasmacytosis but no lytic lesions. Analyses of immunoglobulin synthesis in bone marrow cells from seven patients showed excess light chains in all and incomplete light chains or heavy chain fragments in six, regardless of whether an intact monoclonal protein or related subunit was in the serum or urine. The fibrillar (amyloidotic) and nonfibrillar forms of monoclonal immunoglobulin deposition occur either in overt multiple myeloma or in the course of less neoplastically aggressive plasmacytic dyscrasias. Bone marrow cells from patients with either type produce immunoglobulin fragments that are related to those deposited in the affected tissues.

The presubicular region in Alzheimer's disease: topography of amyloid deposits and neurofibrillary changes

Specific silver impregnation techniques for extracellular amyloid and intraneuronal neurofibrillary changes were used to examine the presubiculum in Alzheimer victims. Extended amyloid clouds in the absence of neurofibrillary changes were noted in the parvopyramidal layer of the presubiculum proper. The corresponding layer in the parasubiculum, in contrast, showed many neurofibrillary tangles and neuropil threads in the absence of amyloid. The transsubicular parvopyramidal layer contained both amyloid deposits and neurofibrillary changes. This severe involvement of all subdivisions of the presubicular region in Alzheimer's disease is considered to impair functions of the Papez circuit.

Differentiated thyroid carcinoma, intermediate type: A new tumor entity with features of follicular and parafollicular cell carcinoma

A group of differentiated thyroid carcinomas with morphologic and immunohistochemical traits of both follicular and medullary carcinoma is described. This group consists of tumors characterized by a solid and/or cribriform histologic pattern with a more or less pronounced admixture of follicular structures, immunohistochemical evidence for the production of thyroglobulin and one or more of the three neurohormonal peptides neurotensin, somatostatin, and calcitonin, and absence of amyloid. These tumors were selected from thyroid carcinomas that had been diagnosed, according to current histopathologic criteria, as differentiated follicular carcinomas. A series of pure follicular carcinomas, devoid of solid or cribriform structures, was found to contain thyroglobulin immunoreactive tumor cells only, whereas a series of classic medullary carcinoma with amyloid stroma revealed specific staining for all three neurohormonal peptides but not for thyroglobulin. The results suggest that differentiated thyroid carcinoma can be regarded as a continuous spectrum of tumor types, with pure follicular carcinomas and classic medullary carcinoma representing the two extremes and the tumors with biphasic features representing a broad intermediate group. The authors suggest that this group be designated "differentiated thyroid carcinoma, intermediate type."

Insular Amyloidosis in Spontaneously Diabetic Nonhuman Primates

Sections of pancreas from 21 nonhuman primates with diabetes mellitus were examined by light and electron microscopy. All monkeys showed amyloid accumulation in the islets of Langerhans. Amyloid was identified by its dichroism with three different stains: Congo red, changing from red to yellowish-green; standardized toluidine blue, changing from blue to red; and sulfated alcian blue, changing from blue-green to pink. Sulfated alcian blue was a rapid and effective means of detecting amyloid. The characteristic fibrillar structure of amyloid was seen with transmission electron microscopy. Deposition of islet amyloid was independent of the presence or absence of amyloid in other organs. Results indicate that nonhuman primates offer a model for studying the sequential development of insular amyloidotic diabetes mellitus.

Lichen Amyloidosus

With the use of new material, lichen amyloidosus was reexamined with improved techniques. Island formation of amyloid in a close spatial relation to fibroblasts and absence of amyloid in perivascular spaces were reemphasized. As new findings, segregation of cytoplasmic material of fibroblast by budding and ballooning of the peripheral cytoplasm, desmosome-like and half-desmosome-like structures of fibroblasts, intracellular amyloid of dermal fibroblasts, and amyloid-like intracellular filaments of keratinocytes were described.

Lichen amyloidosus. Electron microscopic study of a typical case and a review.

With the use of new material, lichen amyloidosus was reexamined with improved techniques. Island formation of amyloid in a close spatial relation to fibroblasts and absence of amyloid in perivascular spaces were reemphasized. As new findings, segregation of cytoplasmic material of fibroblast by budding and ballooning of the peripheral cytoplasm, desmosome-like and half-desmosome-like structures of fibroblasts, intracellular amyloid of dermal fibroblasts, and amyloid-like intracellular filaments of keratinocytes were described.