Search

Introduction: This study characterized the relationship between plasma NfL and cognition in a community-based sample of older Mexican Americans. Methods: 544 participants completed a battery of neuropsychological tests and were diagnosed using clinical criteria. NfL was assayed using Simoa. NfL levels across groups and tests were analyzed. Results: Difference in NfL was found between normal and impaired groups and was related to global cognition, processing speed, executive functions and a list of learning tasks with a significant negative effect for all diagnostic groups. NfL had a negative impact on processing speed, attention, executive functions and delayed and recognition memory for both normal and MCI groups. Conclusion: The research supports plasma NfL as a marker of cognitive impairment related to neurodegenerative processes in Mexican Americans and may be a marker of early changes in cognition in those with normal cognition and at risk for developing MCI.

A cinchona-catalysed, enantioselective oxa-Michael reaction of ,-unsaturated aldehydes with either tert-butyl hydroperoxide or cumene hydroperoxide was developed. The reaction was optimised by screening of solvents, modification of the catalyst framework and variation of the acid co-catalysts. A strong relationship was noted between the pKa of the acid co-catalyst and the degree of selectivity. Enantioselective peroxidation of ,- unsaturated aldehydes with tert-butyl hydroperoxide afforded -peroxyaldehydes with good enantioselectivities. In situ oxidation of the latter compounds furnished -peroxycarboxylic acids in high yields. Enantiomeric excesses were determined by derivitisation to their mandelate esters and subsequent separation by chiral high performance liquid chromatography. Peroxidation with cumene hydroperoxide was similarly successful with the products being isolated as stable -peroxyalcohols. These latter -peroxyalcohols offer a direct route to 5-membered, chiral cycloperoxides via a silver-mediated cyclisation. This reaction proceeds by trapping of the oxygen lone pair by the incipient carbocation followed by loss of the cumyl or tert-butyl group and formation of the cycloperoxide product.

Background: Neuropsychiatric symptoms of dementia are often treated through the prescription of one or more psychotropic medications. However, limited efficacy and potential harmful side-effects has resulted in efforts to reduce the use of psychotropic medication in this population, particularly for those living in long-term care. Objectives: This study sought to describe the pattern of central nervous system medication usage in older adults with dementia living in long-term care; assess the appropriateness of prescribing against Beers criteria; and detect potential drug interactions from co-administered medications. Methods: A retrospective descriptive audit of the medical records of n=415 residents, aged >60 years with a diagnosis of dementia, from 28 long-term care facilities in Queensland, Australia. Information extracted included the types and usage of regular and Pro Re Nata central nervous system medications. Results: Of those taking medication (n=317), 68% were prescribed at least one potentially inappropriate medication, and there was a significant positive correlation between the number of medications prescribed and the number of potentially inappropriate medications. Two-hundred potential interactions with variable severity were identified from 130 residents on ≥1 medication – 38% were potentially severe interactions, 46% were moderate. Conclusion: This medication audit raises concerns that prescription of medications may still be the first resort to treat behavioural and psychological symptoms of dementia. There is a need for effective and sustainable person-centred interventions that address barriers for appropriate prescribing practice, and involve the collaboration of all healthcare professionals to optimise prescribing and improve the quality of medicines in older people with dementia.

Quantitative MRI provides important information about tissue properties in brain both in normal ageing and in degenerative disorders. Although it is well known that those with Alzheimer’s disease (AD) show a specific pattern and faster rate of atrophy than controls, the precise spatial and temporal patterns of quantitative MRI in AD are unknown. We aimed to investigate neuroimaging correlates of AD using serial quantitative MRI. In our study, twenty-one subjects with AD and thirty-two similar-aged healthy controls underwent two serial MRI scans at baseline and 12 months. Tissue characteristics were captured using two quantitative MRI parameters: longitudinal relaxation time (qT1) and transverse relaxation time (qT2). The two groups (AD and controls) were statistically compared using a voxel based quantification (VBQ) method based on Matlab and SPM8. At baseline, subjects with AD showed a significant reduction of qT1 and qT2 compared to controls in bilateral temporal and parietal lobes, hippocampus, and basal ganglia. This pattern was also observed at follow-up. Longitudinally, in AD we found a significant increase rather than further reduction of qT1 and qT2 from the baseline in bilateral hippocampus, thalamus and right caudate nucleus. In addition, the longitudinal change of qT1 in left hippocampus was negatively correlated with cognitive decline in AD over the 1-year period, and the general disease severity significantly predicted the amount of increase of qT1 in bilateral hippocampus over 12 months. The longitudinal change of qT2 in left parahippocampus correlated with change in neuropsychiatric features over time. In summary, quantitative MRI parameters were reduced in AD cross-sectionally, but increased over time, showing distinct spatiotemporal patterns from the atrophy in AD. We also showed the clinical relevance of quantitative MRI parameters, indicating their potential promise as new imaging markers in AD.

The rapidly increasing prevalence of type 2 diabetes (T2D) is motivating an intensive search for biomarkers to identify individuals at risk for developing the disease. It has been established that both genetic and environmental factors are influential in the progression to T2D. Currently, the number of genetic loci implicated in T2D susceptibility is more than 65 and together, these factors explain only about 10% of the risk. At this time, prediction models using genetic information do not perform substantially better than models based on routine clinical measures. The search for new biomarkers must integrate new, independent factors beyond the static genome that are influenced by environmental conditions. This search must also recognize the heterogeneity of T2D and seek new biomarkers of potential subtypes and confounding conditions such as obesity. Modulation of gene expression by epigenetic modifications and the action of microRNAs are being recognized as critical processes affecting T2D risk. This review provides an update on the current state of genetic biomarkers of T2D susceptibility and examines how epigenetic modulation of some new and established diabetes susceptibility genes can identify increased risk and provide biomarkers for early detection and therapeutic monitoring.

Clopidogrel and aspirin are commonly prescribed anti-platelet medications indicated for patients who have experienced, or are at risk for, ischemic cardiovascular events. The Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study was designed to characterize determinants of clopidogrel and dual anti-platelet therapy (DAPT) response in a healthy cohort of Old Order Amish from Lancaster, PA. Following a loading dose, clopidogrel was taken once a day for 7 days. One hour after the last dose of clopidogrel, 325 mg of aspirin was given. Ex vivo platelet aggregometry was performed at baseline, post-clopidogrel, and post-DAPT. Platelet aggregation measurements were significantly lower after both interventions for all agonists tested (p <0.05), although there was large inter-individual variation in the magnitude of anti-platelet response. Female sex and older age were associated with higher platelet aggregation at all three time-points. Change in aggregation was correlated among the various agonists at each time point. Heritability (h2) of change in platelet aggregation was significant for most traits at all time-points (range h2=0.14-0.57). Utilization of a standardized, short-term intervention provided a powerful approach to investigate sources of variation in platelet aggregation response due to drug therapy. Further, this short-term intervention approach may provide a useful paradigm for pharmacogenomics studies.

Background: Electroconvulsive therapy (ECT) is the most effective treatment available for severe depression. However, its mechanisms of action are not yet fully understood. To understand the protein expression changes induced in the hippocampus by this treatment, electroconvulsive stimulation (ECS), the animal model of ECT, was administered chronically (x 10 treatments) to rats. Liquid chromatography tandem mass spectrometry (LC-MS/MS) and label free quantification was used to identify changes in the hippocampal proteome following ECS. Results: In total, 62 proteins were found to be significantly up- or down-regulated following ECS (Student’s t-test, p<0.05). These proteins were organised according to the gene ontology classifications “biological processes”, “molecular functions” and “cellular location”. Conclusions: Primarily cytoskeletal- and energy metabolism-related processes were identified by gene ontology analysis. Proteins with cytoskeletalrelated roles were of particular interest, including the astrocyte marker glial fibrillary acidic protein (GFAP) and microtubule associated proteins (MAPs). These results suggest that ECS administration primarily induces changes in structural and metabolism-associated proteins in the rat hippocampus.

Biomedical research cannot succeed without funding, knowledgeable staff, and appropriate infrastructure. There are however equally important but intangible factors that are rarely considered in planning large multidisciplinary endeavors or evaluating their success. The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial required extensive collaborations between individuals from many fields, including clinicians, clinical trialists, and administrators; it also addressed questions across the spectrum of cancer prevention and control. In this manuscript, we examine the experiences and opinions of trial staff regarding the building of successful relationships in PLCO. We summarize, in narrative form, data collected using open-ended questionnaires that were administered to the National Cancer Institute project officers, coordinating center staff, screening center principal investigators, and screening center coordinators in 2015, about 3 years after publication of the final primary trial manuscript. Trust, respect, listening to others, and in-person interaction were frequently mentioned as crucial to building successful relationships.

The NCI imbedded the notion of comprehensive quality control and assurance (CQA) in the design concept for the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. PLCO implemented a comprehensive, adaptable quality assurance and control program to span more than 20 years of data collection, coordinate multiple institutions and committees, and integrate a wide variety of complex protocols. CQA concepts, practices, and procedures traced through all aspects of trial management, governance, and operations of PLCO. The driving force behind CQA in PLCO was scientific and clinical credibility of trial data and findings. CQA as implemented in PLCO was operationally analogous to the concept of Total Quality Management (TQM) described in the management literature. This paper describes CQA actualization in PLCO.

There were significant recruitment challenges specific to the PLCO Cancer Screening Trial. Large numbers of participants were to be randomized from ten catchment areas nationwide within time and budgetary constraints. The eligible population was elderly and had to meet health and behavioral thresholds. Informed consent was required to participate and be randomized to screening for three cancers at periodic clinic visits or to a usual care arm that included no clinical visits. Consenting required special efforts to fully explain the trial and its potential scientific benefit to future patients with potentially no benefits but possible harms to PLCO participants. Participation would include continued follow-up for at least 13 years after randomization. Strong collaborative investments were required by the NCI and screening centers (SCs) to assure timely recruitment and appropriate racial participation. A trial-wide pilot phase tested recruitment and protocol follow through at SCs and produced a vanguard population of 11,406 participants. NCI announced the trial nationally in advance of the pilot and followed with an even more intense collaborative role with SCs for the main phase to facilitate trial-wide efficient and timely recruitment. Special efforts to enhance recruitment in the main phase included centralized and local monitoring of progress, cross-linking SCs to share experiences in problem solving, centralized training, substantial additional funding dedicated to recruitment and retention, including specialized programs for minority recruitment, obtaining national endorsement by the American Cancer Society, launching satellite recruitment and screening centers, including minority focused satellites, and adding a new SC dedicated to minority recruitment.