Hepatic vascular changes associated with Opisthorchis felineus infection in Syrian hamsters and humans.

The liver fluke Opisthorchis felineus is a foodborne zoonotic pathogen endemic to Russia, Kazakhstan, and several European countries. The adult flukes affect the hepatobiliary system of piscivorous mammals and humans, thereby causing numerous complications, including liver fibrosis. Detailing the mechanisms of progression of the fibrotic complications is a hot topic in the field of research on opisthorchiasis pathogenesis. Pathologic angiogenesis appears to be associated with the fibrogenic progression due to active participation in the recruitment of inflammatory cells and many factors involved in the modulation of the extracellular matrix. The aim of the study was to evaluate neoangiogenesis and amyloid deposits in liver tissues of model animals and patients with confirmed chronic opisthorchiasis. In addition, we assessed a possible correlation of neoangiogenesis with liver fibrosis. We found a significant increase in the number of newly formed vessels and amyloid deposits in the liver of people with chronic opisthorchiasis compared to that of uninfected ones. Thus, for the first time we have demonstrated neoangiogenesis and amyloid deposits during O. felineus infection in a Mesocricetus auratus model. Regression analysis showed that CD34+ newly formed vessels correlate with fibrosis severity in the course of the infection. Our results indicate the potential contribution of angiogenesis to the progression of liver fibrosis, associated with O. felineus infection.

Histological evaluation of the distribution of systemic AA-amyloidosis in nine domestic shorthair cats.

Amyloidosis is a group of protein-misfolding disorders characterized by the accumulation of amyloid in organs, both in humans and animals. AA-amyloidosis is considered a reactive type of amyloidosis and in humans is characterized by the deposition of AA-amyloid fibrils in one or more organs. In domestic shorthair cats, AA-amyloidosis was recently reported to be frequent in shelters. To better characterize this pathology, we report the distribution of amyloid deposits and associated histological lesions in the organs of shelter cats with systemic AA-amyloidosis. AA-amyloid deposits were identified with Congo Red staining and immunofluorescence. AA-amyloid deposits were then described and scored, and associated histological lesions were reported. Based on Congo Red staining and immunofluorescence nine shelter cats presented systemic AA-amyloidosis. The kidney (9/9), the spleen (8/8), the adrenal glands (8/8), the small intestine (7/7) and the liver (8/9) were the organs most involved by amyloid deposits, with multifocal to diffuse and from moderate to severe deposits, both in the organ parenchyma and/or in the vascular compartment. The lung (2/9) and the skin (1/8) were the least frequently involved organs and deposits were mainly focal to multifocal, mild, vascular and perivascular. Interestingly, among the organs with fibril deposition, the stomach (7/9), the gallbladder (6/6), the urinary bladder (3/9), and the heart (6/7) were reported for the first time in cats. All eye, brain and skeletal muscle samples had no amyloid deposits. An inflammatory condition was identified in 8/9 cats, with chronic enteritis and chronic nephritis being the most common. Except for secondary cell compression, other lesions were not associated to amyloid deposits. To conclude, this study gives new insights into the distribution of AA-amyloid deposits in cats. A concurrent chronic inflammation was present in almost all cases, possibly suggesting a relationship with AA-amyloidosis.

The contribution of amyloid deposition in the aortic valve to calcification and aortic stenosis.

Calcific aortic valve disease (CAVD) and stenosis have a complex pathogenesis, and no therapies are available that can halt or slow their progression. Several studies have shown the presence of apolipoprotein-related amyloid deposits in close proximity to calcified areas in diseased aortic valves. In this Perspective, we explore a possible relationship between amyloid deposits, calcification and the development of aortic valve stenosis. These amyloid deposits might contribute to the amplification of the inflammatory cycle in the aortic valve, including extracellular matrix remodelling and myofibroblast and osteoblast-like cell proliferation. Further investigation in this area is needed to characterize the amyloid deposits associated with CAVD, which could allow the use of antisense oligonucleotides and/or isotype gene therapies for the prevention and/or treatment of CAVD.

Diagnosis and Treatment of AL Amyloidosis.

Systemic light chain (AL) amyloidosis is caused by an usually small B cell clone that produces a toxic light chain forming amyloid deposits in tissue. The heart and kidney are the major organs affected, but all others, with the exception of the CNS, can be involved. The disease is rapidly progressive, and it is still diagnosed late. Screening programs in patients followed by hematologists for plasma cell dyscrasias should be considered. The diagnosis requires demonstration in a tissue biopsy of amyloid deposits formed by immunoglobulin light chains. The workup of patients with AL amyloidosis requires adequate technology and expertise, and patients should be referred to specialized centers whenever possible. Stagings are based on cardiac and renal biomarkers and guides the choice of treatment. The combination of daratumumab, cyclophosphamide, bortezomib and dexamethasone (dara-CyBorD) is the current standard of care. Autologous stem cell transplant is performed in eligible patients, especially those who do not attain a satisfactory response to dara-CyBorD. Passive immunotherapy targeting the amyloid deposits combined with chemo-/immune-therapy targeting the amyloid clone is currently being tested in controlled clinical trials. Response to therapy is assessed based on validated criteria. Profound hematologic response is the early goal of treatment and should be accompanied over time by deepening organ response. Many relapsed/refractory patients are also treated with daratumumab combination, but novel regimens will be needed to rescue daratumumab-exposed subjects. Immunomodulatory drugs are the current cornerstone of rescue therapy, while immunotherapy targeting B-cell maturation antigen and inhibitors of Bcl-2 are promising alternatives.

Recent Progress in Research on Mechanisms of Action of Natural Products against Alzheimer's Disease: Dietary Plant Polyphenols.

Alzheimer's disease (AD) is an incurable degenerative disease of the central nervous system and the most common type of dementia in the elderly. Despite years of extensive research efforts, our understanding of the etiology and pathogenesis of AD is still highly limited. Nevertheless, several hypotheses related to risk factors for AD have been proposed. Moreover, plant-derived dietary polyphenols were also shown to exert protective effects against neurodegenerative diseases such as AD. In this review, we summarize the regulatory effects of the most well-known plant-derived dietary polyphenols on several AD-related molecular mechanisms, such as amelioration of oxidative stress injury, inhibition of aberrant glial cell activation to alleviate neuroinflammation, inhibition of the generation and promotion of the clearance of toxic amyloid-ß (Aß) plaques, inhibition of cholinesterase enzyme activity, and increase in acetylcholine levels in the brain. We also discuss the issue of bioavailability and the potential for improvement in this regard. This review is expected to encourage further research on the role of natural dietary plant polyphenols in the treatment of AD.

Traumatic Brain Injury Leads to Alterations in Contusional Cortical miRNAs Involved in Dementia.

There is compelling evidence that head injury is a significant environmental risk factor for Alzheimer's disease (AD) and that a history of traumatic brain injury (TBI) accelerates the onset of AD. Amyloid-ß plaques and tau aggregates have been observed in the post-mortem brains of TBI patients; however, the mechanisms leading to AD neuropathology in TBI are still unknown. In this study, we hypothesized that focal TBI induces changes in miRNA expression in and around affected areas, resulting in the altered expression of genes involved in neurodegeneration and AD pathology. For this purpose, we performed a miRNA array in extracts from rats subjected to experimental TBI, using the controlled cortical impact (CCI) model. In and around the contusion, we observed alterations of miRNAs associated with dementia/AD, compared to the contralateral side. Specifically, the expression of miR-9 was significantly upregulated, while miR-29b, miR-34a, miR-106b, miR-181a and miR-107 were downregulated. Via qPCR, we confirmed these results in an additional group of injured rats when compared to naïve animals. Interestingly, the changes in those miRNAs were concomitant with alterations in the gene expression of mRNAs involved in amyloid generation and tau pathology, such as ß-APP cleaving enzyme (BACE1) and Glycogen synthase-3-ß (GSK3ß). In addition increased levels of neuroinflammatory markers (TNF-α), glial activation, neuronal loss, and tau phosphorylation were observed in pericontusional areas. Therefore, our results suggest that the secondary injury cascade in TBI affects miRNAs regulating the expression of genes involved in AD dementia.

Prognostic value of histopathological scoring and grading in patients with renal AA amyloidosis.

OBJECTIVE: The amount and distribution pattern of amyloid deposits may contribute to renal function and outcome, given the great diversity of renal involvement in amyloidosis. The aim of this study was to analyze the impact of histological characteristics of patients with biopsy-proven renal AA amyloidosis (AAA) on renal outcome. METHODS: Renal biopsies of 37 patients with AAA were re-evaluated. The distribution pattern of glomerular amyloid (GA) deposits was classified, the extent of amyloid deposits in glomeruli, vessel, and interstitium and other histopathologic lesions were scored, and renal amyloid prognostic score (RAPS) was determined by summing all scores. Their potential prognostic relevance on renal outcome was investigated. RESULTS: GA and vascular amyloid (VA) deposits were noted in all cases, interstitial amyloid (IA) was detected in 70.2%. GA deposits were predominantly seen in diffuse mesengiocapillary fashions (class IV) (51.4%). GA class, the extent of GA, VA, IA deposit, and RAPS, as well as interstitial fibrosis (IF) and interstitial inflammation were correlated to renal function at diagnosis. During the median follow-up of 52 months, 13 patients developed doubling of serum creatinine or end stage renal disease and they had a higher degree of GA and VA load (p = 0.03 and p = 0.042, respectively) as compared to the remaining patients. VA load, but not GA and RAPS grade, was associated with poor renal outcome (HR 3.016, 95% CI 1.45-6.25, p = 0.003). CONCLUSIONS: Baseline renal function is closely linked to the extent of AA amyloid deposit in renal parenchyma but only VA load was a predictor of renal outcome in AAA patients.

Renal Involvement in Transthyretin Amyloidosis: The Double Presentation of Transthyretin Amyloidosis Deposition Disease.

Transthyretin (TTR) amyloidosis (ATTR) is either an inherited condition or a non hereditary disease due to misfolding of wild-type (WT) TTR. Amyloid deposits can be mainly detected in nerves in the inherited form and in myocardium in the acquired variant. Renal involvement has been described only in the Val30Met mutation of the familial form and is thought to be extremely rare in the WT TTR. However, ATTR is multi-organ disease, and even in the WT forms, apparently limited to the heart, carpal tunnel syndrome and lumbar or cervical spine amyloid deposition have been described. A series of 4 cases of biopsy-proven renal TTR amyloid deposition is reported in the present paper. We describe 2 WT ATTR patients, 1 patient with c.424G>A (p.(Val142Ile)) mutation of the TTR gene, and 1 patient with Val30Met mutation of the TTR gene. In all patients, the biopsy showed the presence of amyloid deposits with different distribution (#1 pericapsular, #2-3 vessels, #4 vessels, interstitium of medulla and cortex, and tubular basement membrane). The use of immunohistochemistry has enabled the identification of TTR, and identify the precursor protein. The possibility of kidney involvement in TTR amyloidosis should be taken into account in patients with renal impairment and unexplained cardiomyopathy and/or neuropathy. This is even of greater interest to the elderly for the possible confounding co-existence of plasma cell dyscrasia that could lead the clinician, in the presence of renal amyloid deposits, to misdiagnose AL amyloidosis and undertake inappropriate treatments.

Accelerated Aging Characterizes the Early Stage of Alzheimer's Disease.

For Alzheimer's disease (AD), aging is the main risk factor, but whether cognitive impairments due to aging resemble early AD deficits is not yet defined. When working with mouse models of AD, the situation is just as complicated, because only a few studies track the progression of the disease at different ages, and most ignore how the aging process affects control mice. In this work, we addressed this problem by comparing the aging process of PS2APP (AD) and wild-type (WT) mice at the level of spontaneous brain electrical activity under anesthesia. Using local field potential recordings, obtained with a linear probe that traverses the posterior parietal cortex and the entire hippocampus, we analyzed how multiple electrical parameters are modified by aging in AD and WT mice. With this approach, we highlighted AD specific features that appear in young AD mice prior to plaque deposition or that are delayed at 12 and 16 months of age. Furthermore, we identified aging characteristics present in WT mice but also occurring prematurely in young AD mice. In short, we found that reduction in the relative power of slow oscillations (SO) and Low/High power imbalance are linked to an AD phenotype at its onset. The loss of SO connectivity and cortico-hippocampal coupling between SO and higher frequencies as well as the increase in UP-state and burst durations are found in young AD and old WT mice. We show evidence that the aging process is accelerated by the mutant PS2 itself and discuss such changes in relation to amyloidosis and gliosis.

Major Surgery Affects Memory in Individuals with Cerebral Amyloid-ß Pathology.

BACKGROUND: Major surgery has been associated with perioperative neurocognitive disorders (PND), but the contributing factors and long-term prognosis are uncertain. We hypothesize that preclinical Alzheimer's disease (AD) might predispose to cognitive deterioration after surgery. OBJECTIVE: To analyze the effect of amyloid-ß on the cognitive trajectory after orthopedic surgery in a sample of non-demented subjects. METHODS: Non-demented individuals older than 65 years that were on the waiting list for orthopedic surgery with spinal anesthesia underwent a neuropsychological assessment before and after surgery. During surgery, cerebrospinal fluid samples were obtained to determine AD biomarkers. RESULTS: Cumulative incidence of PND was 55.2%during a mean follow-up of nine months. The most affected cognitive domains were executive function and constructional praxis. The presence of abnormal levels of amyloid-ß was associated to a postoperative impairment in verbal and visual memory tests. According to their AD biomarker profile, participants were categorized as either Amyloid Positive (A+) or Amyloid Negative (A-). The incidence of PND did not differ between both groups. The A- group showed a tendency similar to the global sample, worsening in executive function tests and improving on memory scales due to practice effects. In contrast, the A + group showed a notable worsening on memory performance. CONCLUSION: Our findings support the hypothesis that surgery may promote or accelerate memory decline in cognitively asymptomatic subjects with brain amyloid-ß deposits.

Early-Onset Dementia in War Veterans: Brain Polypathology and Clinicopathologic Complexity.

The neuropathology associated with cognitive decline in military personnel exposed to traumatic brain injury (TBI) and chronic stress is incompletely understood. Few studies have examined clinicopathologic correlations between phosphorylated-tau neurofibrillary tangles, ß-amyloid neuritic plaques, neuroinflammation, or white matter (WM) lesions, and neuropsychiatric disorders in veterans. We describe clinicopathologic findings in 4 military veterans with early-onset dementia (EOD) who had varying histories of blunt- and blast-TBI, cognitive decline, behavioral abnormalities, post-traumatic stress disorder, suicidal ideation, and suicide. We found that pathologic lesions in these military-EOD cases could not be categorized as classic Alzheimer's disease (AD), chronic traumatic encephalopathy, traumatic axonal injury, or other well-characterized clinicopathologic entities. Rather, we observed a mixture of polypathology with unusual patterns compared with pathologies found in AD or other dementias. Also, ultrahigh resolution ex vivo MRI in 2 of these 4 brains revealed unusual patterns of periventricular WM injury. These findings suggest that military-EOD cases are associated with atypical combinations of brain lesions and distribution rarely seen in nonmilitary populations. Future prospective studies that acquire neuropsychiatric data before and after deployments, as well as genetic and environmental exposure data, are needed to further elucidate clinicopathologic correlations in military-EOD.

The Austrian Flag - Severe Carpal Tunnel Syndrome: A Case Report.

In severe carpal tunnel syndrome a continuum of neural changes takes place depending on the degree and duration of the compression, beginning with breakdown of the blood-nerve barrier, followed by endoneurial oedema and, subsequently, perineurial thickening and ischemia. Persisting chronic compression will eventually result in axonal degeneration. We report a case of longstanding carpal tunnel syndrome with amyloid deposits and the unusual intraoperative 'Austrian flag' sign.

A Median Nerve Anterior Transposition Procedure for Multi-Recurrent Hemodialysis-Related Carpal Tunnel Syndrome.

BACKGROUND: Some long-term hemodialysis patients suffer from multi-recurrent carpal tunnel syndrome because amyloid originating from ß2-microglobulin continues to be deposited mainly in the flexor tendons, tendon sheaths and flexor retinaculum during maintenance hemodialysis. These amyloid deposits inside carpal canal (tunnel) tissues increase carpal canal pressure and this leads to compression of the median nerve. When multi-recurrent carpal tunnel syndrome occurs, previous operative scarring of soft tissue may prohibit further enlargement of the carpal canal even if any carpal canal decompression procedure is used. For this reason, we developed a median nerve anterior transposition procedure, as a new approach in the treatment of multi-recurrent hemodialysis-related carpal tunnel syndrome. METHODS: Median nerve anterior transposition procedures were performed on seven hands in six patients with multi-recurrent carpal tunnel syndrome. The mean age of the patients was 68.3 years and the mean hemodialysis duration was 35.3 years. Mean follow-up period was 9.9 months. The median nerve is transposed from inside to outside of the carpal canal under local and infiltration anesthesia without a pneumatic tourniquet on an outpatient basis. This procedure is based on the same principles applied in ulnar nerve anterior transposition procedures for cubital tunnel syndrome. RESULTS: Main preoperative patient complaints were intolerable tingling and/or pain in the diseased hands throughout the day. Following the surgeries, preoperative clinical symptoms began to subside and eventually improved in all hands. Postoperative abductor pollicis brevis muscle power using manual muscle testing improved except in one hand. Abnormal preoperative distal motor and sensory latency were improved except in two hands following the surgeries. CONCLUSIONS: The median nerve anterior transposition procedure is a beneficial treatment for patients suffering from hemodialysis-related multi-recurrent carpal tunnel syndrome.

Genome-wide pleiotropy analysis of neuropathological traits related to Alzheimer's disease.

BACKGROUND: Simultaneous consideration of two neuropathological traits related to Alzheimer's disease (AD) has not been attempted in a genome-wide association study. METHODS: We conducted genome-wide pleiotropy analyses using association summary statistics from the Beecham et al. study (PLoS Genet 10:e1004606, 2014) for AD-related neuropathological traits, including neuritic plaque (NP), neurofibrillary tangle (NFT), and cerebral amyloid angiopathy (CAA). Significant findings were further examined by expression quantitative trait locus and differentially expressed gene analyses in AD vs. control brains using gene expression data. RESULTS: Genome-wide significant pleiotropic associations were observed for the joint model of NP and NFT (NP + NFT) with the single-nucleotide polymorphism (SNP) rs34487851 upstream of C2orf40 (alias ECRG4, P = 2.4 × 10-8) and for the joint model of NFT and CAA (NFT + CAA) with the HDAC9 SNP rs79524815 (P = 1.1 × 10-8). Gene-based testing revealed study-wide significant associations (P ≤ 2.0 × 10-6) for the NFT + CAA outcome with adjacent genes TRAPPC12, TRAPPC12-AS1, and ADI1. Risk alleles of proxy SNPs for rs79524815 were associated with significantly lower expression of HDAC9 in the brain (P = 3.0 × 10-3), and HDAC9 was significantly downregulated in subjects with AD compared with control subjects in the prefrontal (P = 7.9 × 10-3) and visual (P = 5.6 × 10-4) cortices. CONCLUSIONS: Our findings suggest that pleiotropy analysis is a useful approach to identifying novel genetic associations with complex diseases and their endophenotypes. Functional studies are needed to determine whether ECRG4 or HDAC9 is plausible as a therapeutic target.

Iron Biochemistry is Correlated with Amyloid Plaque Morphology in an Established Mouse Model of Alzheimer's Disease.

A signature characteristic of Alzheimer's disease (AD) is aggregation of amyloid-beta (Aß) fibrils in the brain. Nevertheless, the links between Aß and AD pathology remain incompletely understood. It has been proposed that neurotoxicity arising from aggregation of the Aß1-42 peptide can in part be explained by metal ion binding interactions. Using advanced X-ray microscopy techniques at sub-micron resolution, we investigated relationships between iron biochemistry and AD pathology in intact cortex from an established mouse model over-producing Aß. We found a direct correlation of amyloid plaque morphology with iron, and evidence for the formation of an iron-amyloid complex. We also show that iron biomineral deposits in the cortical tissue contain the mineral magnetite, and provide evidence that Aß-induced chemical reduction of iron could occur in vivo. Our observations point to the specific role of iron in amyloid deposition and AD pathology, and may impact development of iron-modifying therapeutics for AD.

Astragaloside IV, a Natural PPARγ Agonist, Reduces Aß Production in Alzheimer's Disease Through Inhibition of BACE1.

A number of epidemiological studies have established a link between Alzheimer's disease (AD) and diabetes mellitus (DM). So, nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) plays an important role in the treatment of AD. However, current PPARγ-targeting drugs such as thiazolidinediones (TZDs) are associated with undesirable side effects. We identified herbal extract with a small molecular, astragaloside IV (AS-IV), as a selective PPARγ natural agonist in nervous cells by developing a PPAR-PPRE pathway regulatory system. Cultured SH-SY5Y cells transfected with pEGFP-N1-BACE1 were treated with AS-IV for 24 h or AS-IV plus the PPAR-γ antagonist GW9662 in vitro. APP/PS1 mice were intragastrically treated with AS-IV or AS-IV plus the GW9662 every 48 h for 3 months. Immunofluorescence, western blotting, and real-time PCR were used to examine the expression of PPARγ and BACE1. Immunohistochemical staining was performed to analyze the distribution of Aß plaques in the APP/PS1 mouse brain. The levels of Aß were determined using ELISA kits. AS-IV was shown to be a PPARγ agonist by establishing a high-throughput screening model for PPARγ agonists. The results showed that AS-IV treatment increased activity of PPARγ and inhibited BACE1 in vitro. As a result, Aß levels decreased significantly. GW9662, which is a PPARγ antagonist, significantly blocked the beneficial role of AS-IV. In vivo, AS-IV treatment increased PPARγ and BACE1 expression and reduced neuritic plaque formation and Aß levels in the brains of APP/PS1 mice. These effects of AS-IV could be effectively inhibited by GW9662. These results indicate that AS-IV may be a natural PPARγ agonist that suppressed activity of BACE1 and ultimately attenuates generation of Aß. Therefore, AS-IV may be a promising agent for modulating Aß-related pathology in AD.

Trans-Synaptic Spread of Amyloid-ß in Alzheimer's Disease: Paths to ß-Amyloidosis.

Neuronal activity has a strong causal role in the production and release of the neurotoxic ß-amyloid peptide (Aß). Because of this close link, gradual accumulation of Aß into amyloid plaques has been reported in brain areas with intense neuronal activity, including cortical regions that display elevated activation at resting state. However, the link between Aß and activity is not always linear and recent studies report exceptions to the view of "more activity, more plaques." Here, we review the literature about the activity-dependent production of Aß in both human cases and AD models and focus on the evidences that brain regions with elevated convergence of synaptic connections (herein referred to as brain nodes) are particularly vulnerable to Aß accumulation. Next, we will examine data supporting the hypothesis that, since Aß is released from synaptic terminals, ß-amyloidosis can spread in AD brain by advancing through synaptically connected regions, which makes brain nodes vulnerable to Aß accumulation. Finally, we consider possible mechanisms that account for ß-amyloidosis progression through synaptically linked regions.

A rare presentation of cardiac amyloid deposits isolated to intramural vessels.

The present case illustrates the diagnostic challenges in symptomatic patients with heart failure of unknown etiology. The patients were previously diagnosed with κ-light chain amyloidosis without cardiac involvement. Echocardiography showed heart failure with mildly reduced ejection fraction but no signs of amyloidosis. Coronary angiogram showed normal arteries and 11C-PIB positron emission tomography was negative for amyloid deposits. Exercise testing revealed severe heart failure and reduced coronary flow velocity reserve. Endomyocardial biopsies showed amyloid in the intramural coronary arteries without interstitial amyloid deposits. Hence, the patient was diagnosed with microvascular dysfunction-induced heart failure due to vessel wall amyloidosis.

(68)Ga-Bivalent Polypegylated Styrylpyridine Conjugates for Imaging Aß Plaques in Cerebral Amyloid Angiopathy.

Aß plaques deposited on blood vessels are associated with cerebral amyloid angiopathy (CAA). In an effort to selectively map these Aß plaques, we are reporting a new series of (68)Ga labeled styrylpyridine derivatives with high molecular weights. In vitro binding to Aß plaques in post-mortem Alzheimer's disease (AD) brain tissue showed that these (68)Ga labeled bivalent styrylpyridines displayed good affinities and specificity (Ki < 30 nM). In vitro autoradiography using post-mortem AD brain sections showed specific binding of these (68)Ga complexes to Aß plaques. Biodistribution studies in normal mice showed very low initial brain uptakes (<0.3% dose/g) indicating a low blood-brain barrier (BBB) penetration. The preliminary results suggest that (68)Ga labeled bivalent styrylpyridines may be promising candidates as PET imaging radiotracers for detecting CAA.