The importance of sustained attention in early Alzheimer\u27s disease

Introduction: There is conflicting evidence regarding impairment of sustained attention in early Alzheimer\u27s disease (AD). We examine whether sustained attention is impaired and predicts deficits in other cognitive domains in early AD. Methods: Fifty-one patients with early AD (MMSE \u3e 18) and 15 healthy elderly controls were recruited. The sustained attention to response task (SART) was used to assess sustained attention. A subset of 25 patients also performed tasks assessing general cognitive function (ADAS-Cog), episodic memory (Logical memory scale, Paired Associates Learning), executive function (verbal fluency, grammatical reasoning) and working memory (digit and spatial span). Results: AD patients were significantly impaired on the SART compared to healthy controls (total error β = 19.75, p = 0.027). SART errors significantly correlated with MMSE score (Spearman\u27s rho = −0.338, p = 0.015) and significantly predicted deficits in ADAS-Cog (β = 0.14, p = 0.004). Discussions: Patients with early AD have significant deficits in sustained attention, as measured using the SART. This may impair performance on general cognitive testing, and therefore should be taken into account during clinical assessment, and everyday management of individuals with early AD. Copyright © 2016 John Wiley & Sons, Ltd

Association between MAPT haplotype and memory function in patients with Parkinson's disease and healthy aging individuals.

Genetic variation is associated with differences in the function of the brain as well as its susceptibility to disease. The common H1 haplotypic variant of the microtubule-associated protein tau gene (MAPT) has been related to an increased risk for Parkinson's disease (PD). Furthermore, among PD patients, H1 homozygotes have an accelerated progression to dementia. We investigated the neurocognitive correlates of MAPT haplotypes using functional magnetic resonance imaging. Thirty-seven nondemented patients with PD (19 H1/H1, 18 H2 carriers) and 40 age-matched controls (21 H1/H1, 19 H2 carriers) were scanned during performance of a picture memory encoding task. Behaviorally, H1 homozygosity was associated with impaired picture recognition memory in PD patients and control subjects. These impairments in the H1 homozygotes were accompanied by an altered blood-oxygen level-dependent response in the medial temporal lobe during successful memory encoding. Additional age-related differences in blood-oxygen level-dependent response were observed in the medial temporal lobes of H1 homozygotes with PD. These results suggest that common variation in MAPT is not only associated with the dementia of PD but also differences in the neural circuitry underlying aspects of cognition in normal aging.This work was funded by Parkinson's UK, the Medical Research Council, the Wellcome Trust (088324), and the NIHR Comprehensive Biomedical Research Centre (RG64473). The BCNI is co-funded by the MRC and Wellcome Trust. Sophie E. Winder-Rhodes received PhD funding from a Merck Sharp and Dohme studentship.This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.neurobiolaging.2014.12.006

An Aromatic Dyad Motif in Dye Decolourising Peroxidases Has Implications for Free Radical Formation and Catalysis

Dye decolouring peroxidases (DyPs) are the most recent class of heme peroxidase to be discovered. On reacting with H2O2, DyPs form a high‐valent iron(IV)‐oxo species and a porphyrin radical (Compound I) followed by stepwise oxidation of an organic substrate. In the absence of substrate, the ferryl species decays to form transient protein‐bound radicals on redox active amino acids. Identification of radical sites in DyPs has implications for their oxidative mechanism with substrate. Using a DyP from Streptomyces lividans, referred to as DtpA, which displays low reactivity towards synthetic dyes, activation with H2O2 was explored. A Compound I EPR spectrum was detected, which in the absence of substrate decays to a protein‐bound radical EPR signal. Using a newly developed version of the Tyrosyl Radical Spectra Simulation Algorithm, the radical EPR signal was shown to arise from a pristine tyrosyl radical and not a mixed Trp/Tyr radical that has been widely reported in DyP members exhibiting high activity with synthetic dyes. The radical site was identified as Tyr374, with kinetic studies inferring that although Tyr374 is not on the electron‐transfer pathway from the dye RB19, its replacement with a Phe does severely compromise activity with other organic substrates. These findings hint at the possibility that alternative electron‐transfer pathways for substrate oxidation are operative within the DyP family. In this context, a role for a highly conserved aromatic dyad motif is discussed

COVID-19-Induced Myocarditis: Pathophysiological Roles of ACE2 and Toll-like Receptors

The clinical manifestations of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection responsible for coronavirus disease 2019 (COVID-19) commonly include dyspnoea and fatigue, and they primarily involve the lungs. However, extra-pulmonary organ dysfunctions, particularly affecting the cardiovascular system, have also been observed following COVID-19 infection. In this context, several cardiac complications have been reported, including hypertension, thromboembolism, arrythmia and heart failure, with myocardial injury and myocarditis being the most frequent. These secondary myocardial inflammatory responses appear to be associated with a poorer disease course and increased mortality in patients with severe COVID-19. In addition, numerous episodes of myocarditis have been reported as a complication of COVID-19 mRNA vaccinations, especially in young adult males. Changes in the cell surface expression of angiotensin-converting enzyme 2 (ACE2) and direct injury to cardiomyocytes resulting from exaggerated immune responses to COVID-19 are just some of the mechanisms that may explain the pathogenesis of COVID-19-induced myocarditis. Here, we review the pathophysiological mechanisms underlying myocarditis associated with COVID-19 infection, with a particular focus on the involvement of ACE2 and Toll-like receptors (TLRs)

A frontal attention mechanism in the visual mismatch negativity

Automatic detection of environmental change is a core component of attention. The mismatch negativity (MMN), an electrophysiological marker of this mechanism, has been studied prominently in the auditory domain, with cortical generators identified in temporal and frontal regions. Here, we combined electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) to assess whether the underlying frontal regions associated with auditory change detection also play a role in visual change detection. Twenty healthy young adults completed a visual MMN task in separate EEG and fMRI sessions. Region of interest analyses were conducted on left and right middle frontal (MFG) and inferior frontal (IFG) gyri, i.e., the frontal areas identified as potential auditory MMN generators. A significant increase in activation was observed in the left IFG and MFG in response to blocks containing deviant stimuli. These findings suggest that a frontal mechanism is involved in the detection of change in the visual MMN. Our results support the notion that frontal mechanisms underlie attention switching, as measured via MMN, across multiple modalities

A high-throughput sequencing test for diagnosing inherited bleeding, thrombotic, and platelet disorders.

Inherited bleeding, thrombotic, and platelet disorders (BPDs) are diseases that affect ∼300 individuals per million births. With the exception of hemophilia and von Willebrand disease patients, a molecular analysis for patients with a BPD is often unavailable. Many specialized tests are usually required to reach a putative diagnosis and they are typically performed in a step-wise manner to control costs. This approach causes delays and a conclusive molecular diagnosis is often never reached, which can compromise treatment and impede rapid identification of affected relatives. To address this unmet diagnostic need, we designed a high-throughput sequencing platform targeting 63 genes relevant for BPDs. The platform can call single nucleotide variants, short insertions/deletions, and large copy number variants (though not inversions) which are subjected to automated filtering for diagnostic prioritization, resulting in an average of 5.34 candidate variants per individual. We sequenced 159 and 137 samples, respectively, from cases with and without previously known causal variants. Among the latter group, 61 cases had clinical and laboratory phenotypes indicative of a particular molecular etiology, whereas the remainder had an a priori highly uncertain etiology. All previously detected variants were recapitulated and, when the etiology was suspected but unknown or uncertain, a molecular diagnosis was reached in 56 of 61 and only 8 of 76 cases, respectively. The latter category highlights the need for further research into novel causes of BPDs. The ThromboGenomics platform thus provides an affordable DNA-based test to diagnose patients suspected of having a known inherited BPD.This study, including the enrollment of cases, sequencing, and analysis received support from the National Institute for Health Research (NIHR) BioResource–Rare Diseases. The NIHR BioResource is funded by the NIHR (http://www.nihr.ac.uk). Research in the Ouwehand Laboratory is also supported by grants from Bristol-Myers Squibb, the British Heart Foundation, the British Society of Haematology, the European Commission, the MRC, the NIHR, and the Wellcome Trust; the laboratory also receives funding from National Health Service Blood and Transplant (NHSBT). The clinical fellows received funding from the MRC (C.L. and S.K.W.); the NIHR–Rare Diseases Translational Research Collaboration (S. Sivapalaratnam); and the British Society for Haematology and National Health Service Blood and Transplant (T.K.B.).This is the author accepted manuscript. The final version is available from American Society of Hematology via http://dx.doi.org/10.1182/blood-2015-12-688267

Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses

To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1–11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome