Publications by authors named "Michael Knight"

77 Publications

Structure of an H3N2 influenza virus nucleoprotein.

Acta Crystallogr F Struct Biol Commun 2021 Jul 29;77(Pt 7):208-214. Epub 2021 Jun 29.

Division of Structural Biology, Welcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, United Kingdom.

Influenza A viruses of the H1N1 and H3N2 subtypes are responsible for seasonal epidemic events. The influenza nucleoprotein (NP) binds to the viral genomic RNA and is essential for its replication. Efforts are under way to produce therapeutics and vaccines targeting the NP. Despite this, no structure of an NP from an H3N2 virus has previously been determined. Here, the structure of the A/Northern Territory/60/1968 (H3N2) influenza virus NP is presented at 2.2 Å resolution. The structure is highly similar to those of the A/WSN/1933 (H1N1) and A/Hong Kong/483/97 (H5N1) NPs. Nonconserved amino acids are widely dispersed both at the sequence and structural levels. A movement of the 73-90 RNA-binding loop is observed to be the key difference between the structure determined here and previous structures. The data presented here increase the understanding of structural conservation amongst influenza NPs and may aid in the design of universal interventions against influenza.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1107/S2053230X2100635XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248822PMC
July 2021

Inclusion of cGAMP within virus-like particle vaccines enhances their immunogenicity.

EMBO Rep 2021 Jun 18:e52447. Epub 2021 Jun 18.

Medical Research Council Human Immunology Unit, Radcliffe Department of Medicine, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.

Cyclic GMP-AMP (cGAMP) is an immunostimulatory molecule produced by cGAS that activates STING. cGAMP is an adjuvant when administered alongside antigens. cGAMP is also incorporated into enveloped virus particles during budding. Here, we investigate whether inclusion of cGAMP within viral vaccine vectors enhances their immunogenicity. We immunise mice with virus-like particles (VLPs) containing HIV-1 Gag and the vesicular stomatitis virus envelope glycoprotein G (VSV-G). cGAMP loading of VLPs augments CD4 and CD8 T-cell responses. It also increases VLP- and VSV-G-specific antibody titres in a STING-dependent manner and enhances virus neutralisation, accompanied by increased numbers of T follicular helper cells. Vaccination with cGAMP-loaded VLPs containing haemagglutinin induces high titres of influenza A virus neutralising antibodies and confers protection upon virus challenge. This requires cGAMP inclusion within VLPs and is achieved at markedly reduced cGAMP doses. Similarly, cGAMP loading of VLPs containing the SARS-CoV-2 Spike protein enhances Spike-specific antibody titres. cGAMP-loaded VLPs are thus an attractive platform for vaccination.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.15252/embr.202152447DOI Listing
June 2021

Global analysis of protein-RNA interactions in SARS-CoV-2-infected cells reveals key regulators of infection.

Mol Cell 2021 07 24;81(13):2851-2867.e7. Epub 2021 May 24.

MRC-University of Glasgow Centre for Virus Research, G61 1QH Glasgow, Scotland, UK; Department of Biochemistry, University of Oxford, South Parks Road, OX1 3QU Oxford, UK. Electronic address:

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). SARS-CoV-2 relies on cellular RNA-binding proteins (RBPs) to replicate and spread, although which RBPs control its life cycle remains largely unknown. Here, we employ a multi-omic approach to identify systematically and comprehensively the cellular and viral RBPs that are involved in SARS-CoV-2 infection. We reveal that SARS-CoV-2 infection profoundly remodels the cellular RNA-bound proteome, which includes wide-ranging effects on RNA metabolic pathways, non-canonical RBPs, and antiviral factors. Moreover, we apply a new method to identify the proteins that directly interact with viral RNA, uncovering dozens of cellular RBPs and six viral proteins. Among them are several components of the tRNA ligase complex, which we show regulate SARS-CoV-2 infection. Furthermore, we discover that available drugs targeting host RBPs that interact with SARS-CoV-2 RNA inhibit infection. Collectively, our results uncover a new universe of host-virus interactions with potential for new antiviral therapies against COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.molcel.2021.05.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142890PMC
July 2021

T2 heterogeneity as an in vivo marker of microstructural integrity in medial temporal lobe subfields in ageing and mild cognitive impairment.

Neuroimage 2021 Sep 9;238:118214. Epub 2021 Jun 9.

Bristol Medical School, University of Bristol, Institute of Clinical Neurosciences, Learning & Research Building at Southmead Hospital, Bristol BS10 5NB, UK; Clinical Neurosciences, North Bristol NHS Trust, Bristol, UK.

A better understanding of early brain changes that precede loss of independence in diseases like Alzheimer's disease (AD) is critical for development of disease-modifying therapies. Quantitative MRI, such as T2 relaxometry, can identify microstructural changes relevant to early stages of pathology. Recent evidence suggests heterogeneity of T2 may be a more informative MRI measure of early pathology than absolute T2. Here we test whether T2 markers of brain integrity precede the volume changes we know are present in established AD and whether such changes are most marked in medial temporal lobe (MTL) subfields known to be most affected early in AD. We show that T2 heterogeneity was greater in people with mild cognitive impairment (MCI; n = 49) compared to healthy older controls (n = 99) in all MTL subfields, but this increase was greatest in MTL cortices, and smallest in dentate gyrus. This reflects the spatio-temporal progression of neurodegeneration in AD. T2 heterogeneity in CA1-3 and entorhinal cortex and volume of entorhinal cortex showed some ability to predict cognitive decline, where absolute T2 could not, however further studies are required to verify this result. Increases in T2 heterogeneity in MTL cortices may reflect localised pathological change and may present as one of the earliest detectible brain changes prior to atrophy. Finally, we describe a mechanism by which memory, as measured by accuracy and reaction time on a paired associate learning task, deteriorates with age. Age-related memory deficits were explained in part by lower subfield volumes, which in turn were directly associated with greater T2 heterogeneity. We propose that tissue with high T2 heterogeneity represents extant tissue at risk of permanent damage but with the potential for therapeutic rescue. This has implications for early detection of neurodegenerative diseases and the study of brain-behaviour relationships.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuroimage.2021.118214DOI Listing
September 2021

Weight regulation in menopause.

Menopause 2021 May 24. Epub 2021 May 24.

Division of General Internal Medicine, Department of Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC Department of Internal Medicine, Endocrine Division, Harvard Medical School, Boston, MA Kaiser Permanente-Mid-Atlantic Permanente Medical Group, Washington, DC Departments of Internal Medicine and Pediatrics, Massachusetts General Hospital and Harvard Medical School, Boston, MA Emory College, Emory University, Atlanta, GA Department of Internal Medicine, Neuroendocrine Unit and Department of Pediatrics- Pediatric Endocrinology, MGH Weight Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA.

Importance And Objective: Obesity is a chronic disease of epidemic proportions that continues to affect millions of Americans each year. Postmenopausal women are particularly affected by obesity and have higher rates of severe obesity when compared with their male counterparts. The prevalence of obesity in this population is linked to increased morbidity and mortality and promotes the development and progression of numerous obesity-related health conditions. This review examines the epidemiology, pathophysiology, clinical assessment, and treatment of postmenopausal women with obesity.

Methods: We have reviewed relevant and up-to-date literature in the MEDLINE database to represent the current understanding of obesity and its effects in this patient population. Articles published between the years 2000 and 2020 were selected for review to represent the most up-to-date evidence on the topic. Search terms used in the PubMed search included women, obesity, menopause, aging, mid-age women, metabolism, weight gain, treatment of obesity, weight loss, bariatric surgery, weight loss medications, diet, physical activity, and behavior modification.

Discussion And Conclusion: Obesity is a complex, chronic, relapsing disease that requires comprehensive assessment and treatment. Obesity is linked to hormonal, lifestyle, and environmental changes that occur during the menopausal transition, and it increases the risk for cardiometabolic disease. The utilization of appropriate clinical evaluation methods to identify obesity in postmenopausal women, and the implementation of effective lifestyle, pharmacotherapeutic, and surgical interventions, have the propensity to reduce the deleterious effects of obesity in this population.

Video Summary:http://links.lww.com/MENO/A770.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/GME.0000000000001792DOI Listing
May 2021

The antigenic anatomy of SARS-CoV-2 receptor binding domain.

Cell 2021 04 18;184(8):2183-2200.e22. Epub 2021 Feb 18.

MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK.

Antibodies are crucial to immune protection against SARS-CoV-2, with some in emergency use as therapeutics. Here, we identify 377 human monoclonal antibodies (mAbs) recognizing the virus spike and focus mainly on 80 that bind the receptor binding domain (RBD). We devise a competition data-driven method to map RBD binding sites. We find that although antibody binding sites are widely dispersed, neutralizing antibody binding is focused, with nearly all highly inhibitory mAbs (IC < 0.1 μg/mL) blocking receptor interaction, except for one that binds a unique epitope in the N-terminal domain. Many of these neutralizing mAbs use public V-genes and are close to germline. We dissect the structural basis of recognition for this large panel of antibodies through X-ray crystallography and cryoelectron microscopy of 19 Fab-antigen structures. We find novel binding modes for some potently inhibitory antibodies and demonstrate that strongly neutralizing mAbs protect, prophylactically or therapeutically, in animal models.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2021.02.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891125PMC
April 2021

Breadth and function of antibody response to acute SARS-CoV-2 infection in humans.

PLoS Pathog 2021 02 26;17(2):e1009352. Epub 2021 Feb 26.

MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.

Serological and plasmablast responses and plasmablast-derived IgG monoclonal antibodies (MAbs) have been analysed in three COVID-19 patients with different clinical severities. Potent humoral responses were detected within 3 weeks of onset of illness in all patients and the serological titre was elicited soon after or concomitantly with peripheral plasmablast response. An average of 13.7% and 3.5% of plasmablast-derived MAbs were reactive with virus spike glycoprotein or nucleocapsid, respectively. A subset of anti-spike (10 of 32) antibodies cross-reacted with other betacoronaviruses tested and harboured extensive somatic mutations, indicative of an expansion of memory B cells upon SARS-CoV-2 infection. Fourteen of 32 anti-spike MAbs, including five anti-receptor-binding domain (RBD), three anti-non-RBD S1 and six anti-S2, neutralised wild-type SARS-CoV-2 in independent assays. Anti-RBD MAbs were further grouped into four cross-inhibiting clusters, of which six antibodies from three separate clusters blocked the binding of RBD to ACE2 and five were neutralising. All ACE2-blocking anti-RBD antibodies were isolated from two recovered patients with prolonged fever, which is compatible with substantial ACE2-blocking response in their sera. Finally, the identification of non-competing pairs of neutralising antibodies would offer potential templates for the development of prophylactic and therapeutic agents against SARS-CoV-2.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.ppat.1009352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130932PMC
February 2021

Photoinduced cross-linking of formulation buffer amino acids to monoclonal antibodies.

Eur J Pharm Biopharm 2021 Mar 26;160:35-41. Epub 2021 Jan 26.

Biomolecular Formulation and Characterization Sciences, UCB, Slough SL3WE, UK.

The correct choice of formulation buffer is a critical aspect of drug development and is chosen primarily to improve the stability of a protein therapeutic and protect against degradation. Amino acids are frequently incorporated into formulation buffers. In this study we have identified and characterized light induced cross-links between the side chain of histidine residues in an IgG4 monoclonal antibody and different amino acids commonly used in formulation buffers. These reactions have the potential to impact the overall product quality of the drug. The structure of each cross-link identified was elucidated using high performance liquid chromatography (HPLC) hyphenated to tandem mass spectrometry (MS/MS) with higher energy collisional dissociation (HCD). Furthermore, we speculate on the role of amino acids in formulation buffers and their influence on mAb stability. We theorize that whilst the adduction of formulation buffer amino acids could have a negative impact on product quality, it may protect against other pathways of photo-degradation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejpb.2021.01.011DOI Listing
March 2021

Correlative Multi-scale Cryo-imaging Unveils SARS-CoV-2 Assembly and Egress.

Res Sq 2021 Jan 19. Epub 2021 Jan 19.

Since the outbreak of the SARS-CoV-2 pandemic, there have been intense structural studies on purified recombinant viral components and inactivated viruses. However, structural and ultrastructural evidence on how the SARS-CoV-2 infection progresses in the frozen-hydrated native cellular context is scarce, and there is a lack of comprehensive knowledge on the SARS-CoV-2 replicative cycle. To correlate the cytopathic events induced by SARS-CoV-2 with virus replication process under the frozen-hydrated condition, here we established a unique multi-modal, multi-scale cryo-correlative platform to image SARS-CoV-2 infection in Vero cells. This platform combines serial cryoFIB/SEM volume imaging and soft X-ray cryo-tomography with cell lamellae-based cryo-electron tomography (cryoET) and subtomogram averaging. The results place critical SARS-CoV-2 structural events â€" e.g. viral RNA transport portals on double membrane vesicles, virus assembly and budding intermediates, virus egress pathways, and native virus spike structures from intracellular assembled and extracellular released virus - in the context of whole-cell images. The latter revealed numerous heterogeneous cytoplasmic vesicles, the formation of membrane tunnels through which viruses exit, and the drastic cytoplasm invasion into the nucleus. This integrated approach allows a holistic view of SARS-CoV-2 infection, from the whole cell to individual molecules.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21203/rs.3.rs-134794/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836121PMC
January 2021

SARS-CoV-2 RNA detected in blood products from patients with COVID-19 is not associated with infectious virus.

Wellcome Open Res 2020 12;5:181. Epub 2020 Oct 12.

Nuffield Department of Medicine, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK.

Laboratory diagnosis of SARS-CoV-2 infection (the cause of COVID-19) uses PCR to detect viral RNA (vRNA) in respiratory samples. SARS-CoV-2 RNA has also been detected in other sample types, but there is limited understanding of the clinical or laboratory significance of its detection in blood. We undertook a systematic literature review to assimilate the evidence for the frequency of vRNA in blood, and to identify associated clinical characteristics. We performed RT-PCR in serum samples from a UK clinical cohort of acute and convalescent COVID-19 cases (n=212), together with convalescent plasma samples collected by NHS Blood and Transplant (NHSBT) (n=462 additional samples). To determine whether PCR-positive blood samples could pose an infection risk, we attempted virus isolation from a subset of RNA-positive samples. We identified 28 relevant studies, reporting SARS-CoV-2 RNA in 0-76% of blood samples; pooled estimate 10% (95%CI 5-18%). Among serum samples from our clinical cohort, 27/212 (12.7%) had SARS-CoV-2 RNA detected by RT-PCR. RNA detection occurred in samples up to day 20 post symptom onset, and was associated with more severe disease (multivariable odds ratio 7.5). Across all samples collected ≥28 days post symptom onset, 0/494 (0%, 95%CI 0-0.7%) had vRNA detected. Among our PCR-positive samples, cycle threshold (ct) values were high (range 33.5-44.8), suggesting low vRNA copy numbers. PCR-positive sera inoculated into cell culture did not produce any cytopathic effect or yield an increase in detectable SARS-CoV-2 RNA. There was a relationship between RT-PCR negativity and the presence of total SARS-CoV-2 antibody (p=0.02). vRNA was detectable at low viral loads in a minority of serum samples collected in acute infection, but was not associated with infectious SARS-CoV-2 (within the limitations of the assays used). This work helps to inform biosafety precautions for handling blood products from patients with current or previous COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.12688/wellcomeopenres.16002.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689603PMC
October 2020

SARS-CoV-2 Assembly and Egress Pathway Revealed by Correlative Multi-modal Multi-scale Cryo-imaging.

bioRxiv 2020 Nov 5. Epub 2020 Nov 5.

Since the outbreak of the SARS-CoV-2 pandemic, there have been intense structural studies on purified recombinant viral components and inactivated viruses. However, investigation of the SARS-CoV-2 infection in the native cellular context is scarce, and there is a lack of comprehensive knowledge on SARS-CoV-2 replicative cycle. Understanding the genome replication, assembly and egress of SARS-CoV-2, a multistage process that involves different cellular compartments and the activity of many viral and cellular proteins, is critically important as it bears the means of medical intervention to stop infection. Here, we investigated SARS-CoV-2 replication in Vero cells under the near-native frozen-hydrated condition using a unique correlative multi-modal, multi-scale cryo-imaging approach combining soft X-ray cryo-tomography and serial cryoFIB/SEM volume imaging of the entire SARS-CoV-2 infected cell with cryo-electron tomography (cryoET) of cellular lamellae and cell periphery, as well as structure determination of viral components by subtomogram averaging. Our results reveal at the whole cell level profound cytopathic effects of SARS-CoV-2 infection, exemplified by a large amount of heterogeneous vesicles in the cytoplasm for RNA synthesis and virus assembly, formation of membrane tunnels through which viruses exit, and drastic cytoplasm invasion into nucleus. Furthermore, cryoET of cell lamellae reveals how viral RNAs are transported from double-membrane vesicles where they are synthesized to viral assembly sites; how viral spikes and RNPs assist in virus assembly and budding; and how fully assembled virus particles exit the cell, thus stablishing a model of SARS-CoV-2 genome replication, virus assembly and egress pathways.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/2020.11.05.370239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654880PMC
November 2020

Multimodal Response to Copper Binding in Superoxide Dismutase Dynamics.

J Am Chem Soc 2020 11 9;142(46):19660-19667. Epub 2020 Nov 9.

Centre de RMN à Très Hauts Champs, FRE 2034 (CNRS/Université Claude Bernard Lyon 1/Ecole Normale Supérieure de Lyon), University of Lyon, 69100 Villeurbanne, France.

Copper/zinc superoxide dismutase (SOD) is a homodimeric metalloenzyme that has been extensively studied as a benchmark for structure-function relationships in proteins, in particular because of its implication in the familial form of the neurodegenerative disease amyotrophic lateral sclerosis. Here, we investigate microcrystalline preparations of two differently metalated forms of SOD, namely, the fully mature functional Cu,Zn state and the E,Zn-SOD state in which the Cu site is empty. By using solid-state NMR with fast magic-angle spinning (MAS) at high magnetic fields (H Larmor frequency of 800-1000 MHz), we quantify motions spanning a dynamic range from ns to ms. We determine that metal ion uptake does not act as a rigidification element but as a switch redistributing motional processes on different time scales, with coupling of the dynamics of histidine side chains and those of remote key backbone elements of the protein.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jacs.0c09242DOI Listing
November 2020

Risk factors associated with splenectomy following a blunt splenic injury in pediatric patients.

Pediatr Surg Int 2020 Dec 12;36(12):1459-1464. Epub 2020 Oct 12.

Division of Trauma and Surgical Critical Care, Jersey Shore University Medical Center, 1945 State Route 33, Neptune, NJ, 07754, USA.

Purpose: The purpose of the study was to identify the factors associated with splenectomy in pediatric trauma patients.

Method: Pediatric Trauma quality improvement program (P-TQIP) database calendar year 2014-2016 was accessed for the study. All patients, age ≤ 18 years old, who sustained splenic injury due to blunt mechanism, were included in the study. The primary outcome of the study was to identify the risk factors associated with splenectomy. Univariate followed by multivariate analyses were performed. A p value of < 0.05 was considered an indication of statistical significance.

Results: Of 1297 trauma victims, who fulfilled the inclusion criteria, 57 (4.4%) patients underwent total splenectomy. In Univariate analysis, there were significant differences found, in many variables, between the groups who underwent splenectomy versus those who did not have splenectomy. A multivariate logistic regression analysis showed use of blood transfusion within 4 h and severity of splenic injury were the two variables associated with splenectomy. The area under the curve (AUC) value was 0.892 and the 95% confidence intervals were [0.859, 0.923].

Conclusion: Blood transfusion within 4 h of patient's arrival to the hospital and high-grade splenic injury were main factors for splenectomy in the pediatric population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00383-020-04750-9DOI Listing
December 2020

Accelerated long-term forgetting in healthy older adults predicts cognitive decline over 1 year.

Alzheimers Res Ther 2020 09 28;12(1):119. Epub 2020 Sep 28.

Bristol Medical School, University of Bristol, Bristol, UK.

Background: Here, we address a pivotal factor in Alzheimer's prevention-identifying those at risk early, when dementia can still be avoided. Recent research highlights an accelerated forgetting phenotype as a risk factor for Alzheimer's disease. We hypothesized that delayed recall over 4 weeks would predict cognitive decline over 1 year better than 30-min delayed recall, the current gold standard for detecting episodic memory problems which could be an early clinical manifestation of incipient Alzheimer's disease. We also expected hippocampal subfield volumes to improve predictive accuracy.

Methods: Forty-six cognitively healthy older people (mean age 70.7 ± 7.97, 21/46 female), recruited from databases such as Join Dementia Research, or a local database of volunteers, performed 3 memory tasks on which delayed recall was tested after 30 min and 4 weeks, as well as Addenbrooke's Cognitive Examination III (ACE-III) and CANTAB Paired Associates Learning. Medial temporal lobe subregion volumes were automatically measured using high-resolution 3T MRI. The ACE-III was repeated after 12 months to assess the change in cognitive ability. We used univariate linear regressions and ROC curves to assess the ability of tests of delayed recall to predict cognitive decline on ACE-III over the 12 months.

Results: Fifteen of the 46 participants declined over the year (≥ 3 points lost on ACE-III). Four-week verbal memory predicted cognitive decline in healthy older people better than clinical gold standard memory tests and hippocampal MRI. The best single-test predictor of cognitive decline was the 4-week delayed recall on the world list (R = .123, p = .018, β = .418). Combined with hippocampal subfield volumetry, 4-week verbal recall identifies those at risk of cognitive decline with 93% sensitivity and 86% specificity (AUC = .918, p < .0001).

Conclusions: We show that a test of accelerated long-term forgetting over 4 weeks can predict cognitive decline in healthy older people where traditional tests of delayed recall cannot. Accelerated long-term forgetting is a sensitive, easy-to-test predictor of cognitive decline in healthy older people. Used alone or with hippocampal MRI, accelerated forgetting probes functionally relevant Alzheimer's-related change. Accelerated forgetting will identify early-stage impairment, helping to target more invasive and expensive molecular biomarker testing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13195-020-00693-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523317PMC
September 2020

A Comparison of T Relaxation-Based MRI Stroke Timing Methods in Hyperacute Ischemic Stroke Patients: A Pilot Study.

J Cent Nerv Syst Dis 2020 12;12:1179573520943314. Epub 2020 Sep 12.

Faculty of Engineering, University of Bristol, Bristol, UK.

Background: T relaxation-based magnetic resonance imaging (MRI) signals may provide onset time for acute ischemic strokes with an unknown onset. The ability of visual and quantitative MRI-based methods in a cohort of hyperacute ischemic stroke patients was studied.

Methods: A total of 35 patients underwent 3T (3 Tesla) MRI (<9-hour symptom onset). Diffusion-weighted (DWI), apparent diffusion coefficient (ADC), T-weighted (Tw), T-weighted (Tw), and T relaxation time (T) images were acquired. T-weighted fluid attenuation inversion recovery (FLAIR) images were acquired for 17 of these patients. Image intensity ratios of the average intensities in ischemic and non-ischemic reference regions were calculated for ADC, DWI, Tw, T relaxation, and FLAIR images, and optimal image intensity ratio cut-offs were determined. DWI and FLAIR images were assessed visually for DWI/FLAIR mismatch.

Results: The T relaxation time image intensity ratio was the only parameter with significant correlation with stroke duration ( = 0.49,  = .003), an area under the receiver operating characteristic curve (AUC = 0.77,  < .0001), and an optimal cut-off (T ratio = 1.072) that accurately identified patients within the 4.5-hour thrombolysis treatment window with sensitivity of 0.74 and specificity of 0.74. In the patients with the additional FLAIR, areas under the precision-recall-gain curve (AUPRG) and F scores showed that the T relaxation time ratio (AUPRG = 0.60, F = 0.73) performed considerably better than the FLAIR ratio (AUPRG = 0.39, F = 0.57) and the visual DWI/FLAIR mismatch (F = 0.25).

Conclusions: Quantitative T relaxation time is the preferred MRI parameter in the assessment of patients with unknown onset for treatment stratification.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1179573520943314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488882PMC
September 2020

T2 heterogeneity: a novel marker of microstructural integrity associated with cognitive decline in people with mild cognitive impairment.

Alzheimers Res Ther 2020 09 10;12(1):105. Epub 2020 Sep 10.

Bristol Medical School, University of Bristol, Bristol, UK.

Background: Early Alzheimer's disease (AD) diagnosis is vital for development of disease-modifying therapies. Prior to significant brain tissue atrophy, several microstructural changes take place as a result of Alzheimer's pathology. These include deposition of amyloid, tau and iron, as well as altered water homeostasis in tissue and some cell death. T2 relaxation time, a quantitative MRI measure, is sensitive to these changes and may be a useful non-invasive, early marker of tissue integrity which could predict conversion to dementia. We propose that different microstructural changes affect T2 in opposing ways, such that average 'midpoint' measures of T2 are less sensitive than measuring distribution width (heterogeneity). T2 heterogeneity in the brain may present a sensitive early marker of AD pathology.

Methods: In this cohort study, we tested 97 healthy older controls, 49 people with mild cognitive impairment (MCI) and 10 with a clinical diagnosis of AD. All participants underwent structural MRI including a multi-echo sequence for quantitative T2 assessment. Cognitive change over 1 year was assessed in 20 participants with MCI. T2 distributions were modelled in the hippocampus and thalamus using log-logistic distribution giving measures of log-median value (midpoint; T2μ) and distribution width (heterogeneity; T2σ).

Results: We show an increase in T2 heterogeneity (T2σ; p < .0001) in MCI compared to healthy controls, which was not seen with midpoint (T2μ; p = .149) in the hippocampus and thalamus. Hippocampal T2 heterogeneity predicted cognitive decline over 1 year in MCI participants (p = .018), but midpoint (p = .132) and volume (p = .315) did not. Age affects T2, but the effects described here are significant even after correcting for age.

Conclusions: We show that T2 heterogeneity can identify subtle changes in microstructural integrity of brain tissue in MCI and predict cognitive decline over a year. We describe a new model that considers the competing effects of factors that both increase and decrease T2. These two opposing forces suggest that previous conclusions based on T2 midpoint may have obscured the true potential of T2 as a marker of subtle neuropathology. We propose that T2 heterogeneity reflects microstructural integrity with potential to be a widely used early biomarker of conditions such as AD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13195-020-00672-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488446PMC
September 2020

Picometer Resolution Structure of the Coordination Sphere in the Metal-Binding Site in a Metalloprotein by NMR.

J Am Chem Soc 2020 09 19;142(39):16757-16765. Epub 2020 Sep 19.

Université de Lyon, Centre de RMN à Très Hauts Champs, FRE 2034 CNRS/Université Claude Bernard Lyon 1/ENS Lyon, 5 rue de la Doua, Villeurbanne 69100, France.

Most of our understanding of chemistry derives from atomic-level structures obtained with single-crystal X-ray diffraction. Metal centers in X-ray structures of small organometallic or coordination complexes are often extremely well-defined, with errors in the positions on the order of 10-10 Å. Determining the metal coordination geometry to high accuracy is essential for understanding metal center reactivity, as even small structural changes can dramatically alter the metal activity. In contrast, the resolution of X-ray structures in proteins is limited typically to the order of 10 Å. This resolution is often not sufficient to develop precise structure-activity relations for the metal sites in proteins, because the uncertainty in positions can cover all of the known ranges of bond lengths and bond angles for a given type of metal complex. Here we introduce a new approach that enables the determination of a high-definition structure of the active site of a metalloprotein from a powder sample, by combining magic-angle spinning (MAS) nuclear magnetic resonance (NMR) spectroscopy, tailored radio frequency (RF) irradiation schemes, and computational approaches. This allows us to overcome the "blind sphere" in paramagnetic proteins, and to observe and assign H, C, and N resonances for the ligands directly coordinating the metal center. We illustrate the method by determining the bond lengths in the structure of the Co coordination sphere at the core of human superoxide dismutase 1 (SOD) with 0.7 pm precision. The coordination geometry of the resulting structure explains the nonreactive nature of the Co/Zn centers in these proteins, which allows them to play a purely structural role.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jacs.0c07339DOI Listing
September 2020

Monoclonal antibody stability can be usefully monitored using the excitation-energy-dependent fluorescence edge-shift.

Biochem J 2020 09;477(18):3599-3612

Department of Biology and Biochemistry, University of Bath, Bath, U.K.

Among the major challenges in the development of biopharmaceuticals are structural heterogeneity and aggregation. The development of a successful therapeutic monoclonal antibody (mAb) requires both a highly active and also stable molecule. Whilst a range of experimental (biophysical) approaches exist to track changes in stability of proteins, routine prediction of stability remains challenging. The fluorescence red edge excitation shift (REES) phenomenon is sensitive to a range of changes in protein structure. Based on recent work, we have found that quantifying the REES effect is extremely sensitive to changes in protein conformational state and dynamics. Given the extreme sensitivity, potentially this tool could provide a 'fingerprint' of the structure and stability of a protein. Such a tool would be useful in the discovery and development of biopharamceuticals and so we have explored our hypothesis with a panel of therapeutic mAbs. We demonstrate that the quantified REES data show remarkable sensitivity, being able to discern between structurally identical antibodies and showing sensitivity to unfolding and aggregation. The approach works across a broad concentration range (µg-mg/ml) and is highly consistent. We show that the approach can be applied alongside traditional characterisation testing within the context of a forced degradation study (FDS). Most importantly, we demonstrate the approach is able to predict the stability of mAbs both in the short (hours), medium (days) and long-term (months). The quantified REES data will find immediate use in the biopharmaceutical industry in quality assurance, formulation and development. The approach benefits from low technical complexity, is rapid and uses instrumentation which exists in most biochemistry laboratories without modification.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1042/BCJ20200580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527260PMC
September 2020

A novel biparatopic hybrid antibody-ACE2 fusion that blocks SARS-CoV-2 infection: implications for therapy.

MAbs 2020 Jan-Dec;12(1):1804241

New Drug Discovery and Development, Biotheus Inc , Zhuhai, China.

In the absence of a proven effective vaccine preventing infection by SARS-CoV-2, or a proven drug to treat COVID-19, the positive results of passive immune therapy using convalescent serum provide a strong lead. We have developed a new class of tetravalent, biparatopic therapy, 89C8-ACE2. It combines the specificity of a monoclonal antibody (89C8) that recognizes the relatively conserved N-terminal domain of the viral Spike (S) glycoprotein, and the ectodomain of ACE2, which binds to the receptor-binding domain of S. This molecule shows exceptional performance , inhibiting the interaction of recombinant S1 to ACE2 and transduction of ACE2-overexpressing cells by S-pseudotyped lentivirus with IC50s substantially below 100 pM, and with potency approximately 100-fold greater than ACE2-Fc itself. Moreover, 89C8-ACE2 was able to neutralize authentic viral infection in a standard 96-h co-incubation assay at low nanomolar concentrations, making this class of molecule a promising lead for therapeutic applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/19420862.2020.1804241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7531490PMC
August 2020

Structural basis for the neutralization of SARS-CoV-2 by an antibody from a convalescent patient.

Nat Struct Mol Biol 2020 10 31;27(10):950-958. Epub 2020 Jul 31.

William Dunn School of Pathology, University of Oxford, Oxford, UK.

The COVID-19 pandemic has had an unprecedented health and economic impact and there are currently no approved therapies. We have isolated an antibody, EY6A, from an individual convalescing from COVID-19 and have shown that it neutralizes SARS-CoV-2 and cross-reacts with SARS-CoV-1. EY6A Fab binds the receptor binding domain (RBD) of the viral spike glycoprotein tightly (K of 2 nM), and a 2.6-Å-resolution crystal structure of an RBD-EY6A Fab complex identifies the highly conserved epitope, away from the ACE2 receptor binding site. Residues within this footprint are key to stabilizing the pre-fusion spike. Cryo-EM analyses of the pre-fusion spike incubated with EY6A Fab reveal a complex of the intact spike trimer with three Fabs bound and two further multimeric forms comprising the destabilized spike attached to Fab. EY6A binds what is probably a major neutralizing epitope, making it a candidate therapeutic for COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41594-020-0480-yDOI Listing
October 2020

Neutralizing nanobodies bind SARS-CoV-2 spike RBD and block interaction with ACE2.

Nat Struct Mol Biol 2020 09 13;27(9):846-854. Epub 2020 Jul 13.

MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.

The SARS-CoV-2 virus is more transmissible than previous coronaviruses and causes a more serious illness than influenza. The SARS-CoV-2 receptor binding domain (RBD) of the spike protein binds to the human angiotensin-converting enzyme 2 (ACE2) receptor as a prelude to viral entry into the cell. Using a naive llama single-domain antibody library and PCR-based maturation, we have produced two closely related nanobodies, H11-D4 and H11-H4, that bind RBD (K of 39 and 12 nM, respectively) and block its interaction with ACE2. Single-particle cryo-EM revealed that both nanobodies bind to all three RBDs in the spike trimer. Crystal structures of each nanobody-RBD complex revealed how both nanobodies recognize the same epitope, which partly overlaps with the ACE2 binding surface, explaining the blocking of the RBD-ACE2 interaction. Nanobody-Fc fusions showed neutralizing activity against SARS-CoV-2 (4-6 nM for H11-H4, 18 nM for H11-D4) and additive neutralization with the SARS-CoV-1/2 antibody CR3022.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41594-020-0469-6DOI Listing
September 2020

Discovery of a Photoinduced Histidine-Histidine Cross-Link in an IgG4 Antibody.

J Am Soc Mass Spectrom 2020 Jun 22;31(6):1233-1240. Epub 2020 May 22.

Biomolecular Formulation and Characterization Sciences, UCB Group, Slough, SL3WE, United Kingdom.

A novel histidine-histidine (His-His) photooxidative cross-link has been identified in an IgG4 antibody. It was formed between the side chain of a histidine residue of the antibody and histidine from the formulation buffer. The structure of the cross-link was elucidated using high performance liquid chromatography (HPLC) hyphenated to tandem mass spectrometry (MS/MS) with higher energy collisional dissociation (HCD). The cross-link was found in multiple conformations, as the location of the oxygen varied. Furthermore, the extent of cross-link formation was shown to correlate with the amount of light the antibody was exposed to as well as the solvent accessibility of each modification site.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jasms.0c00076DOI Listing
June 2020

Comparative Molecular Biology Approaches for the Production of Poliovirus Virus-Like Particles Using .

mSphere 2020 03 11;5(2). Epub 2020 Mar 11.

School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom

For enteroviruses such as poliovirus (PV), empty capsids, which are antigenically indistinguishable from mature virions, are produced naturally during viral infection. The production of such capsids recombinantly, in heterologous systems such as yeast, have great potential as virus-like particle (VLP) vaccine candidates. Here, using PV as an exemplar, we show the production of VLPs in by coexpression of the structural precursor protein P1 and the viral protease 3CD. The level of expression of the potentially cytotoxic protease relative to that of the P1 precursor was modulated by three different approaches: expression of the P1 precursor and protease from different transcription units, separation of the P1 and protease proteins using the virus (TaV) 2A translation interruption sequence, or separation of the P1 and protease-coding sequences by an internal ribosome entry site sequence from virus (RhPV). We also investigate the antigenicity of VLPs containing previously characterized mutations when produced in Finally, using transmission electron microscopy and two-dimensional classification, we show that -derived VLPs exhibited the classical icosahedral capsid structure displayed by enteroviruses. Although the current poliovirus immunization program has been extremely successful in reducing the number of cases of paralytic polio worldwide, now more cases are caused by vaccine-derived polioviruses than by wild poliovirus. Switching to inactivated poliovirus vaccines will reduce this over time; however, their production requires the growth of large amounts of virus. This biosafety concern can be addressed by producing just the virus capsid. The capsid serves to protect the genetic material, which causes disease when introduced into a cell. Therefore, empty capsids (virus-like particles [VLPs]), which lack the viral RNA genome, are safe both to make and to use. We exploit yeast as a versatile model expression system to produce VLPs, and here we specifically highlight the potential of this system to supply next-generation poliovirus vaccines to secure a polio-free world for the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/mSphere.00838-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7067596PMC
March 2020

Prospective memory in prodromal Alzheimer's disease: Real world relevance and correlations with cortical thickness and hippocampal subfield volumes.

Neuroimage Clin 2020 22;26:102226. Epub 2020 Feb 22.

Bristol Medical School, University of Bristol, Bristol, UK; Clinical Neurosciences, North Bristol NHS Trust, Bristol, UK.

Introduction: Prospective memory (PM) is a marker of independent living in Alzheimer's disease. PM requires cue identification (prospective component) and remembering what should happen in response to the cue (retrospective component). We assessed neuroanatomical basis and functional relevance of PM.

Methods: 84 older participants (53-94 years old, 58% male) with or without Mild Cognitive Impairment (MCI) performed PM tests, Activities of Daily Living (ADL) scale and had a structural MRI of the brain to estimate for cortical thickness and hippocampal subfield volumes. A General Linear Model cluster analysis was carried out using FreeSurfer to determine which cortical regions were correlated with PM scores.

Results: Both components of PM are impaired in MCI (p < .001). The retrospective component of PM correlates strongly with ADL (p = .005). Prospective component performance correlates positively with cortical thickness of bilateral frontal-temporal-parietal cortex and volume of CA1 of hippocampus. In contrast, the retrospective component performance correlates positively with cortical thickness of a right-lateralised fronto-temporal-parietal network and volumes of subiculum and CA3 hippocampal subfields.

Discussion: Our neuroimaging findings complement and extend previous research into structural correlates of PM. Here, we show that there are distinct, yet, overlapping brain regions correlating with the two components of PM. PM performance provides a window into real-life functional abilities in people at risk of Alzheimer's disease and could be utilised as a marker of clinically relevant disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nicl.2020.102226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063259PMC
February 2021

The structure of the influenza A virus genome.

Nat Microbiol 2019 11 22;4(11):1781-1789. Epub 2019 Jul 22.

Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.

Influenza A viruses (IAVs) constitute a major threat to human health. The IAV genome consists of eight single-stranded viral RNA segments contained in separate viral ribonucleoprotein (vRNP) complexes that are packaged together into a single virus particle. The structure of viral RNA is believed to play a role in assembling the different vRNPs into budding virions and in directing reassortment between IAVs. Reassortment between established human IAVs and IAVs harboured in the animal reservoir can lead to the emergence of pandemic influenza strains to which there is little pre-existing immunity in the human population. While previous studies have revealed the overall organization of the proteins within vRNPs, characterization of viral RNA structure using conventional structural methods is hampered by limited resolution and an inability to resolve dynamic components. Here, we employ multiple high-throughput sequencing approaches to generate a global high-resolution structure of the IAV genome. We show that different IAV genome segments acquire distinct RNA conformations and form both intra- and intersegment RNA interactions inside influenza virions. We use our detailed map of IAV genome structure to provide direct evidence for how intersegment RNA interactions drive vRNP cosegregation during reassortment between different IAV strains. The work presented here is a roadmap both for the development of improved vaccine strains and for the creation of a framework to 'risk assess' reassortment potential to better predict the emergence of new pandemic influenza strains.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41564-019-0513-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191640PMC
November 2019

Determining T2 relaxation time and stroke onset relationship in ischaemic stroke within apparent diffusion coefficient-defined lesions. A user-independent method for quantifying the impact of stroke in the human brain.

Biomed Spectrosc Imaging 2019 Jul;8(1-2):11-28

School of Experimental Psychology, University of Bristol, Bristol, UK; Stroke Medicine, Southmead Hospital, North Bristol NHS Trust, Bristol, UK.

Background And Objective: In hyperacute ischaemic stroke, T2 of cerebral water increases with time. Quantifying this change may be informative of the extent of tissue damage and onset time. Our objective was to develop a user-unbiased method to measure the effect of cerebral ischaemia on T2 to study stroke onset time-dependency in human acute stroke lesions.

Methods: Six rats were subjected to permanent middle cerebral occlusion to induce focal ischaemia, and a consecutive cohort of acute stroke patients (n = 38) were recruited within 9 hours from symptom onset. T1-weighted structural, T2 relaxometry, and diffusion MRI for apparent diffusion coefficient (ADC) were acquired. Ischaemic lesions were defined as regions of lowered ADC. The median T2 difference (ΔT2) between lesion and contralateral non-ischaemic control region was determined by the newly-developed spherical reference method, and data compared to that obtained by the mirror reference method. Linear regressions and receiver operating characteristics (ROC) were compared between the two methods.

Results: ΔT2 increases linearly in rat brain ischaemia by 1.9 ± 0.8 ms/h during the first 6 hours, as determined by the spherical reference method. In patients, ΔT2 linearly increases by 1.6 ± 1.4 and 1.9 ± 0.9 ms/h in the lesion, as determined by the mirror reference and spherical reference method, respectively. ROC analyses produced areas under the curve of 0.83 and 0.71 for the spherical and mirror reference methods, respectively.

Conclusions: Data from the spherical reference method showed that the median T2 increase in the ischaemic lesion is correlated with stroke onset time in a rat as well as in a human patient cohort, opening the possibility of using the approach as a timing tool in clinics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/bsi-190185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6640032PMC
July 2019

Quantifying T relaxation time changes within lesions defined by apparent diffusion coefficient in grey and white matter in acute stroke patients.

Phys Med Biol 2019 04 29;64(9):095016. Epub 2019 Apr 29.

School of Psychological Science, University of Bristol, 12a Priory Rd, Bristol BS8 1TU, United Kingdom.

The apparent diffusion coefficient (ADC) of cerebral water, as measured by diffusion MRI, rapidly decreases in ischaemia, highlighting a lesion in acute stroke patients. The MRI T relaxation time changes in ischaemic brain such that T in ADC lesions may be informative of the extent of tissue damage, potentially aiding in stratification for treatment. We have developed a novel user-unbiased method of determining the changes in T in ADC lesions as a function of clinical symptom duration based on voxel-wise referencing to a contralateral brain volume. The spherical reference method calculates the most probable pre-ischaemic T on a voxel-wise basis, making use of features of the contralateral hemisphere presumed to be largely unaffected. We studied whether T changes in the two main cerebral tissue types, i.e. in grey matter (GM) and white matter (WM), would differ in stroke. Thirty-eight acute stroke patients were accrued within 9 h of symptom onset and scanned at 3 T for 3D T -weighted, multi b-value diffusion and multi-echo spin echo MRI for tissue type segmentation, quantitative ADC and absolute T images, respectively. T changes measured by the spherical reference method were 1.94  ±  0.61, 1.50  ±  0.52 and 1.40  ±  0.54 ms h in the whole, GM, and WM lesions, respectively. Thus, T time courses were comparable between GM and WM independent of brain tissue type involved. We demonstrate that T changes in ADC-delineated lesions can be quantified in the clinical setting in a user unbiased manner and that T change correlated with symptom onset time, opening the possibility of using the approach as a tool to assess severity of tissue damage in the clinical setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1088/1361-6560/ab1442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520250PMC
April 2019

Novel Blood Biomarkers that Correlate with Cognitive Performance and Hippocampal Volumetry: Potential for Early Diagnosis of Alzheimer's Disease.

J Alzheimers Dis 2019 ;67(3):931-947

Faculty of Health and Life Sciences, University of the West of England, Bristol, UK.

Background: Differential diagnosis of people presenting with mild cognitive impairment (MCI) that will progress to Alzheimer's disease (AD) remains clinically challenging. Current criteria used to define AD include a series of neuropsychological assessments together with relevant imaging analysis such as magnetic resonance imaging (MRI). The clinical sensitivity and specificity of these assessments would be improved by the concomitant use of novel serum biomarkers. The branched chain aminotransferase proteins (BCAT) are potential candidates as they are significantly elevated in AD brain, correlate with Braak Stage, and may have a role in AD pathology.

Objective: In this hypothesis-driven project, we aimed to establish if serum BCAT and its metabolites are significantly altered in AD participants and assess their role as markers of disease pathology.

Methods: Serum amino acids were measured using a triple quadrupole mass spectrometer for tandem mass spectroscopy together with BCAT levels using western blot analysis, coupled with neuropsychological assessments and MRI.

Results: We present data supporting a substantive mutually correlated system between BCAT and glutamate, neuropsychological tests, and MRI for the diagnosis of AD. These three domains, individually, and in combination, show good utility in discriminating between groups. Our model indicates that BCAT and glutamate accurately distinguish between control and AD participants and in combination with the neuropsychological assessment, MoCA, improved the overall sensitivity to 1.00 and specificity to 0.978.

Conclusion: These findings indicate that BCAT and glutamate have potential to improve the clinical utility and predictive power of existing methods of AD assessment and hold promise as early indicators of disease pathology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JAD-180879DOI Listing
May 2020
-->