Alzheimer's Disease Biomarkers Revisited From the Amyloid Cascade Hypothesis Standpoint

Alzheimer’s disease (AD) is the most common neurodegenerative disease worldwide. Amyloid beta (Aβ) is one of the proteins which aggregate in AD, and its key role in the disease pathogenesis is highlighted in the amyloid cascade hypothesis, which states that the deposition of Aβ in the brain parenchyma is a crucial initiating step in the future development of AD. The sensitivity of instruments used to measure proteins in blood and cerebrospinal fluid has significantly improved, such that Aβ can now successfully be measured in plasma. However, due to the peripheral production of Aβ, there is significant overlap between diagnostic groups. The presence of pathological Aβ within the AD brain has several effects on the cells and surrounding tissue. Therefore, there is a possibility that using markers of tissue responses to Aβ may reveal more information about Aβ pathology and pathogenesis than looking at plasma Aβ alone. In this manuscript, using the amyloid cascade hypothesis as a starting point, we will delve into how the effect of Aβ on the surrounding tissue can be monitored using biomarkers. In particular, we will consider whether glial fibrillary acidic protein, triggering receptor expressed on myeloid cells 2, phosphorylated tau, and neurofilament light chain could be used to phenotype and quantify the tissue response against Aβ pathology in AD

Binding Small Molecules to a cis-Dicarbonyl 99^{\text{99}}TcITc^{\text{I}}-PNP Complex via Metal–Ligand Cooperativity

Metal–ligand cooperativity is a powerful tool for the activation of various bonds but has rarely, if ever, been studied with the radioactive transition metal $^{\text{99}}$Tc. In this work, we explore this bond activation pathway with the dearomatized PNP complex cis-[99TcI(PyrPNPtBu*)(CO)2] (4), which was synthesized by deprotonation of trans-[99TcI(PyrPNPtBu)(CO)2Cl] with KOtBu. Analogous to its rhenium congener, the dearomatized compound reacts with CO2 to form the carboxy complex cis-[99TcI(PyrPNPtBu–COO)(CO)2] and with H2 to form the mono-hydride complex cis-[99TcI(PyrPNPtBu)(CO)2H] (7). Substrates with weakly acidic protons are deprotonated by the Brønsted basic pincer backbone of 4, yielding a variety of intriguing complexes. Reactions with terminal alkynes enable the isolation of acetylide complexes. The deprotonation of an imidazolium salt results in the in situ formation and coordination of a carbene ligand. Furthermore, a study with heterocyclic substrates allowed for the isolation of pyrrolide and pyrazolide complexes, which is uncommon for Tc. The spectroscopic analyses and their solid-state structures are reported

Towards 99mTc- and Re-based multifunctional silica platforms for theranostic applications

Taking advantage of the radiation properties of 99mTc and 186/188Re and the photophysical characteristics of the {M(CO)3}+ moiety (M = Re), we developed a multifunctional silica platform with the theranostic pair 99mTc/Re with high potential for (nano)medical applications. Starting with a general screening to evaluate the most suitable mesoporous silica construct and the development of appropriate chelate systems, multifunctional mesoporous silica microparticles (SBA-15) were synthesized. These particles act as a model towards the synthesis of the corresponding nanoconstructs. The particles can be modified at the external surface with a targeting function and labeled with the {M(CO)3}+ moiety (M = 99mTc, Re) at the pore surface. Thus, a silica platform is realized, whose bioprofile is not altered by the loaded modalities. The described synthetic procedures can be applied to establish a target-specific theranostic nanoplatform, which enables the combination of fluorescence and radio imaging, with the possibility of radio- and chemotherapy

Serum Neurofilament Light and Multiple Sclerosis Progression Independent of Acute Inflammation

Introduction Efforts to explore the utility of neurofilament light (NfL) as a biomarker associated with disability progression in multiple sclerosis (MS) have accelerated in recent years in the absence of pharmacodynamic or treatment response markers for clinical trials or patient care.1 The International Progressive MS Alliance stated in 2020 that serum NfL (sNfL) measurements may serve as a useful biomarker associated with progressive MS, although further work is needed to define the relative contributions of inflammatory activity and neurodegeneration to longitudinal changes in disability and sNfL.2 Using data from a large clinical trial of patients with secondary progressive MS (a phase 3, randomized, double-blind, placebo-controlled trial exploring the effect of natalizumab on disease progression in participants with Secondary Progressive Multiple Sclerosis [ASCEND in SPMS]; NCT01416181), we investigated whether sNfL could be used as a dynamic biomarker associated with progressive MS disease course. That is, we investigated whether longitudinal changes in sNfL concentration were associated with disability progression measures in the absence of relapses and magnetic resonance imaging (MRI) evidence of inflammatory activit

Parallel Data Mining on Multicore Clusters”, gcc

Abstract-The ever increasing number of cores per chip will be accompanied by a pervasive data deluge whose size will probably increase even faster than CPU core count over the next few years. This suggests the importance of parallel data analysis and data mining applications with good multicore, cluster and grid performance. This paper considers data clustering, mixture models and dimensional reduction presenting a unified framework applicable to bioinformatics, cheminformatics and demographics. Deterministic annealing is used to lessen effect of local minima. We present performance results on clusters of 2-8 core systems identifying effects from cache, runtime fluctuations, synchronization and memory bandwidth. We discuss needed programming model and compare with MPI and other approaches

Acceptability and feasibility of plasma phosphorylated-tau181 in two memory services

BACKGROUND: Plasma phosphorylated-tau181 (p-tau181) represents a novel blood-based biomarker of Alzheimer's disease pathology. We explored clinicians' experience of the utility of plasma p-tau181 in Camden and Islington Memory Services. METHODS: Patients were identified by their clinician as appropriate for p-tau181. Their p-tau181 result was plotted on a reference range graph provided to clinicians. This was discussed with the patient at diagnostic feedback appointment. RESULTS: Twenty-nine participants' plasma p-tau181 samples were included (mean age 74 SD 8.5, 65% female). Nine clinicians participated in the study. Eighty-six percent of clinicians found the p-tau181 result to be helpful and in 93% of cases it was clearly understandable. The p-tau181 result was useful in making the diagnosis in 44% of cases. CONCLUSIONS: Plasma p-tau181 is a feasible test for use in memory services and acceptable to clinicians. Clinician feedback on utility in dementia diagnoses was mixed. Further work is required to provide education and training in understanding and interpreting ambiguity in biomarker results

BRain health and healthy AgeINg in retired rugby union players, the BRAIN Study: study protocol for an observational study in the UK.

INTRODUCTION: Relatively little is known about the long-term health of former elite rugby players, or former sportspeople more generally. As well as the potential benefits of being former elite sportspersons, there may be potential health risks from exposures occurring during an individual's playing career, as well as following retirement. Each contact sport has vastly different playing dynamics, therefore exposing its players to different types of potential traumas. Current evidence suggests that these are not necessarily comparable in terms of pathophysiology, and their potential long-term adverse effects might also differ. There is currently limited but increasing evidence that poorer age-related and neurological health exists among former professional sportsmen exposed to repetitive concussions; however the evidence is limited on rugby union players, specifically. METHODS AND ANALYSIS: We present the protocol for a cross-sectional study to assess the association between self-reported history of concussion during a playing career, and subsequent measures of healthy ageing and neurological and cognitive impairment. We are recruiting a sample of approximately 200 retired rugby players (former Oxford and Cambridge University rugby players and members of the England Rugby International Club) aged 50 years or more, and collecting a number of general and neurological health-related outcome measures though validated assessments. Biomarkers of neurodegeneration (neurofilaments and tau) will be also be measured. Although the study is focusing on rugby union players specifically, the general study design and the methods for assessing neurological health are likely to be relevant to other studies of former elite sportspersons. ETHICS AND DISSEMINATION: The study has been approved by the Ethical Committee of London School of Hygiene and Tropical Medicine (reference: 11634-2). It is intended that results of this study will be published in peer-reviewed medical journals, communicated to participants, the general public and all relevant stakeholders

The PSEN1 E280G mutation leads to increased amyloid-β43 production in induced pluripotent stem cell neurons and deposition in brain tissue

Mutations in the presenilin 1 gene, PSEN1, which cause familial Alzheimer’s disease alter processing of amyloid precursor protein, leading to the generation of various amyloid-β peptide species. These species differ in their potential for aggregation. Mutation-specific amyloid-β peptide profiles may thereby influence pathogenicity and clinical heterogeneity. There is particular interest in comparing mutations with typical and atypical clinical presentations, such as E280G. We generated PSEN1 E280G mutation induced pluripotent stem cells from two patients and differentiated them into cortical neurons, along with previously reported PSEN1 M146I, PSEN1 R278I and two control lines. We assessed both the amyloid-β peptide profiles and presenilin 1 protein maturity. We also compared amyloid-β peptide profiles in human post-mortem brain tissue from cases with matched mutations. Amyloid-β ratios significantly differed compared with controls and between different patients, implicating mutation-specific alterations in amyloid-β ratios. Amyloid-β42:40 was increased in the M146I and both E280G lines compared with controls. Amyloid-β42:40 was not increased in the R278I line compared with controls. The amyloid-β43:40 ratio was increased in R278I and both E280G lines compared with controls, but not in M146I cells. Distinct amyloid-β peptide patterns were also observed in human brain tissue from individuals with these mutations, showing some similar patterns to cell line observations. Reduced presenilin 1 maturation was observed in neurons with the PSEN1 R278I and E280G mutations, but not the M146I mutation. These results suggest that mutation location can differentially alter the presenilin 1 protein and affect its autoendoproteolysis and processivity, contributing to the pathological phenotype. Investigating differences in underlying molecular mechanisms of familial Alzheimer’s disease may inform our understanding of clinical heterogeneity