Background-We evaluated the amounts of amyloid-beta (Aβ) peptides in the central nervous system (CNS) and in reservoirs outside the CNS and their potential impact on Aβ plasma levels and Alzheimer's disease (AD) pathology.

Experiments with amyloid-␤ (A␤)-42-immunized transgenic mouse models of Alzheimer's disease have revealed amyloid plaque disruption and apparent cognitive function recovery. Neuropathological examination of patients vaccinated against purified A␤-42 (AN-1792) has demonstrated that senile plaque disruption occurred in immunized humans as well. Here, we examined tissue histology and quantified and biochemically characterized the remnant amyloid peptides in the gray and white matter and leptomeningeal/cortical vessels of two AN-1792-vaccinated patients, one of whom developed meningoencephalitis. Compact core and diffuse amyloid deposits in both vaccinated individuals were focally absent in some regions. Although parenchymal amyloid was focally disaggregated, vascular deposits were relatively preserved or even increased. Immunoassay revealed that total soluble amyloid levels were sharply elevated in vaccinated patient gray and white matter compared with Alzheimer's disease cases. Our experiments suggest that although immunization disrupted amyloid deposits, vascular capture prevented largescale egress of A␤ peptides. Trapped, solubilized amyloid peptides may ultimately have cascading toxic effects on cerebrovascular, gray and white matter tissues. Anti-amyloid immunization may be most effective not as therapeutic or mitigating measures but as a prophylactic measure when A␤ deposition is still minimal. This may allow A␤ mobilization under conditions in which drainage and degradation of these toxic peptides is efficient.

Background: Mutations in the presenilin (PSEN) genes are associated with early-onset familial Alzheimer's disease (FAD). Biochemical characterizations and comparisons have revealed that many PSEN mutations alter γ-secretase activity to promote accumulation of toxic Aβ42 peptides. In this study, we compared the histopathologic and biochemical profiles of ten FAD cases expressing independent PSEN mutations and determined the degradation patterns of amyloid-β precursor protein (AβPP), Notch, N-cadherin and Erb-B4 by γ-secretase. In addition, the levels of Aβ40/42 peptides were quantified by ELISA.

BackgroundActive and passive immunotherapy in both amyloid-beta precursor protein (APP) transgenic mice and Alzheimer's Disease (AD) patients have resulted in remarkable reductions in amyloid plaque accumulation, although the degree of amyloid regression has been highly variable. Nine individuals with a clinical diagnosis of AD dementia were actively immunized with the Aβ peptide 1-42 (AN-1792) and subjected to detailed postmortem biochemical analyses. These patients were compared to 6 non-immunized AD cases and 5 non-demented control (NDC) cases.ResultsAll patients were assessed for the presence of AD pathology including amyloid plaques, neurofibrillary tangles and vascular amyloidosis. This effort revealed that two immunotherapy recipients had dementia as a consequence of diseases other than AD. Direct neuropathological examination consistently demonstrated small to extensive areas in which amyloid plaques apparently were disrupted. Characterization of Aβ species remnants by ELISA suggested that total Aβ levels may have been reduced, although because the amounts of Aβ peptides among treated individuals were extremely variable, those data must be regarded as tentative. Chromatographic analysis and Western blots revealed abundant dimeric Aβ peptides. SELDI-TOF mass spectrometry demonstrated a substantive number of Aβ-related peptides, some of them with elongated C-terminal sequences. Pro-inflammatory TNF-α levels were significantly increased in the gray matter of immunized AD cases compared to the NDC and non-immunized AD groups.ConclusionsImmunotherapy responses were characterized by extreme variability. Considering the broad range of biological variation that characterizes aging and complicates the recognition of reliable AD biomarkers, such disparities will make the interpretation of outcomes derived from epidemiologic and therapeutic investigations challenging. Although in some cases the apparent removal of amyloid plaques by AN-1792 was impressive, proportionate alterations in the clinical progression of AD were not evident. The fact that plaque elimination did not alter the trajectory of decline into dementia suggests the likelihood that these deposits alone are not the underlying cause of dementia.

Alzheimer's disease (AD) is characterized by the accumulation of extracellular insoluble amyloid, primarily derived from polymerized amyloid-␤ (A␤) peptides. We characterized the chemical composition of the A␤ peptides deposited in the brain parenchyma and cerebrovascular walls of triple transgenic Tg-SwDI mice that produce a rapid and profuse A␤ accumulation. The processing of the N-and C-terminal regions of mutant A␤PP differs substantially from humans because the brain parenchyma accumulates numerous, diffuse, nonfibrillar plaques, whereas the thalamic microvessels harbor overwhelming amounts of compact, fibrillar, thioflavine-S-and apolipoprotein E-positive amyloid deposits. The abundant accretion of vascular amyloid, despite low A␤PP transgene expression levels, suggests that inefficient A␤ proteolysis because of conformational changes and dimerization may be key pathogenic factors in this animal model. The disruption of amyloid plaque cores by immunotherapy is accompanied by increased perivascular deposition in both humans and transgenic mice. This analogous susceptibility and response to the disruption of amyloid deposits suggests that Tg-SwDI mice provide an excellent model in which to study the functional aftermath of immunotherapeutic interventions. These mice might also reveal new avenues to promote amyloidogenic A␤PP processing and fundamental insights into the faulty degradation and clearance of A␤ in AD, pivotal issues in understanding AD pathophysiology and the assessment of new therapeutic agents. Alzheimer's disease (AD) dementia is affecting an escalating proportion of the elderly population because of a dramatic increase in life expectancy. This neurodegenerative disorder is characterized by the profuse accumulation of extracellular insoluble amyloid in cerebral vessels and senile plaques, which are mainly composed of amyloid fibrils derived from polymerized amyloid-␤ (A␤) peptides. Amyloid-␤40/42 peptides are generated from the proteolytic degradation of the amyloid-␤ precursor protein (A␤PP) by the action of the ␤-and ␥-secretases. Amyloid-␤ peptides are very insoluble and resistant to subsequent proteolytic degradation because they contain a segment of the hydrophobic transmembrane domain of A␤PP. The prominent amyloid buildup associated with AD has resulted in the amyloid cascade hypothesis in which amyloid plays a fundamental mechanistic role in the pathogenesis and the emergence of dementia. A second relevant lesion in the AD brain is the accumulation of neurofibrillary tangles and neuropil threads that are mainly composed of hyperphosphorylated tau, a microtubule-associated protein.To determine the mechanisms leading to amyloid deposition and its clearance as well as its pathophysiological effects on brain tissue, several transgenic (Tg) mice have been engineered that carry familial AD A␤PP mutations with suitable promoters to accelerate the deposition of A␤

Cancer cachexia is an unmet clinical need that affects more than 50% of patients with cancer. The systemic inflammatory response, which is mediated by a network of cytokines, has an established role in the genesis and maintenance of cancer as well as in cachexia; yet, the specific role of the cytokine milieu in cachexia requires elucidation. This systematic review aims to examine the relationship between cytokines and the cachexia syndrome in patients with incurable cancer. The databases MEDLINE, EMBASE, CINAHL, CENTRAL, PsycINFO, and Web of Science were searched for studies published between 01/01/2004 and 06/01/2020. Included studies measured cytokines and their relationship with cachexia and related symptoms/signs in adults with incurable cancer. After title screening (n = 5202), the abstracts (n = 1264) and the full-text studies (n = 322) were reviewed independently by two authors. The quality assessment of the selected papers was conducted using the modified Downs and Black checklist. Overall, 1277 patients with incurable cancer and 155 healthy controls were analysed in the 17 eligible studies. The mean age of the patients was 64 ± 15 (mean ± standard deviation). Only 34% of included participants were female. The included studies were assessed as moderate-quality to high-quality evidence (mean quality score: 7.8; range: 5-10). A total of 31 cytokines were examined in this review, of which interleukin-6 (IL-6, 14 studies) and tumour necrosis factor-α (TNF-α, 12 studies) were the most common. The definitions of cachexia and the weight-loss thresholds were highly variable across studies. Although the data could not be meta-analysed due to the high degree of methodological heterogeneity, the findings were discussed in a systematic manner. IL-6, TNF-α, and IL-8 were greater in cachectic patients compared with healthy individuals. Also, IL-6 levels were higher in cachectic participants as opposed to non-cachectic patients. Leptin, interferon-γ, IL-1β, IL-10, adiponectin, and ghrelin did not demonstrate any significant difference between groups when individuals with cancer cachexia were compared against non-cachectic patients or healthy participants. These findings suggest that a network of cytokines, commonly IL-6, TNF-α, and IL-8, are associated with the development of cachexia. Yet, this relationship is not proven to be causative and future studies should opt for longitudinal designs with consistent methodological approaches, as well as adequate techniques for analysing and reporting the results.

Background In the United Kingdom, national guidance published in 2010 recommended the establishment of specialist teams to improve clinical pathways for patients presenting with malignancies of undefined primary origin (MUO) and cancer of unknown primary (CUP). This study sought to define outcomes of patients referred to a regional MUO/CUP service. Methods Data were collected prospectively on all patients (n = 1225) referred to a regional CUP team over a 10-year period. Patient demographics, clinical, pathological and outcome data were recorded and analysed. Results Confirmed CUP (cCUP) was diagnosed in 25% of patients. A primary metastatic cancer was identified in 36%, 5% were diagnosed with provisional CUP (pCUP), 27% retained the diagnosis of MUO and in 8% a non-cancer diagnosis was made. Median survival was low in all patients with a final malignant diagnosis: primary identified 9.0 months, cCUP 4.0 months, pCUP 1.5 months and MUO 1.5 months. Conclusions Patients presenting with MUO have poor outcomes irrespective of the final diagnosis. These patients need a patient-centred, streamlined, rapid diagnostic pathway. There are clear benefits to primary and secondary care teams having access to a dedicated, multidisciplinary MUO/CUP service, with clinical nurse specialists supporting the patients, to help facilitate this pathway and ensure early oncology review.

We investigated the morphology and biochemistry of the amyloid-beta (Abeta) peptides produced in TgCRND8 Tg mice carrying combined amyloid precursor protein (APP) Swedish (K670M/N671L) and Indiana (V717F) mutations. Histological analyses employing amyloid-specific staining and electron microscopy revealed that the TgCRND8 Tg mice produce an aggressive pathology, evident as early as 3 months of age, that is a composite of core plaques and peculiar floccular diffuse parenchymal deposits. The Abeta peptides were purified using combined FPLC-HPLC, Western blots, and immunoprecipitation methods and characterized by MALDI-TOF/SELDI-TOF mass spectrometry. The C-terminal APP peptides, assessed by Western blot experiments and mass spectrometry, suggested an alteration in the order of secretase processing, yielding a C-terminal fragment pattern that is substantially different from that observed in sporadic Alzheimer's disease (AD). This modified processing pattern generated longer Abeta peptides, as well as those ending at residues 40/42/43, which may partially explain the early onset and destructive nature of familial AD caused by APP mutations. Despite an aggressive pathology that extended to the cerebellum and white matter, these animals tolerated the presence of an imposing amount of Abeta load. Abeta immunization resulted in an impressive 7-fold reduction in the number of amyloid core plaques and, as previously demonstrated, a significant memory recovery. However, given the phylogenetic distance and the differences in APP processing and Abeta chemistry between Tg mice and AD, caution should be applied in projecting mouse therapeutic interventions onto human subjects.