Michael J. Knight

• Doctor of Philosophy
• Senior Data Scientist at Malvern Panalytical

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 b...

Unknown onset time is a common contraindication for anti-thrombolytic treatment of ischaemic stroke.T2 relaxation-based signal changes within the lesion can identify patients within or beyond the 4.5-hour intravenous thrombolysis treatment-window. However, now that intra-arterial thrombolysis is recommended between 4.5 and 6 hours from symptom onse...

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 t...

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 b...

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...

Background: T2 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)...

Abstract 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 c...

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 10-4-10-5 Å. Determining the metal coordination geometry to hig...

Early Alzheimer's disease diagnosis is vital for development of disease-modifying therapies. Prior to significant loss of brain tissue, 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...

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 o...

The apparent diffusion coefficient (ADC) of cerebral water decreases in ischaemia within minutes, making it suitable for delineating lesions in acute stroke patients. The T2 relaxation time, however, changes on a longer time-scale such that it can be used to estimate onset time. It is also potentially informative of the extent of tissue damage and...

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 T2 relaxation time changes in ischaemic brain such that T2 in ADC lesions may be informative of the extent of tissue damage, potentially aiding in stratification for treatm...

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 strok...

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 clinica...

Background and objective: Multiple factors including chemical composition and microstructure influence relaxivity of tissue water in vivo. We have quantified T1 in the human white mater (WM) together with diffusion tensor imaging to study a possible relationship between water T1, diffusional fractional anisotropy (FA) and fibre-to-field angle. Me...

Background Quantitative T2 and diffusion MRI indices inform about tissue state and microstructure, both of which may be affected by pathology before tissue atrophy. Purpose To evaluate the capability of both volumetric and quantitative MRI (qMRI) of the hippocampus and entorhinal cortex (EC) for classification of amnestic mild cognitive impairment...

Apparent diffusion coefficient (ADC) decreases in the ischaemic brain within minutes, but provides no information about onset time in the early hours of stroke. Instead, absolute T2 relaxation time changes in a time-dependent manner in ADC lesions and might therefore potentially serve as a proxy for onset time and support clinical decisions in pati...

BACKGROUND AND PURPOSE Incomplete hippocampal inversion (IHI) is an atypical anatomical pattern presented by the hippocampus. It is associated with several neuropathological conditions and is thought to be a factor of susceptibility to hippocampal sclerosis and loss of volume. The volume loss of hippocampus is an inevitable consequence of aging, an...

Background and purpose: Preterm birth is associated with worse neurodevelopmental outcome, but brain maturation in preterm infants is poorly characterized with standard methods. We evaluated white matter (WM) of infant brains at term-equivalent age, as a function of gestational age at birth, using multimodal magnetic resonance imaging (MRI). Meth...

Both recognition of familiar objects and pattern separation, a process that orthogonalises overlapping events, are critical for effective memory. Evidence is emerging that human pattern separation requires dentate gyrus. Dentate gyrus is intimately connected to CA3 where, in animals, an autoassociative network enables recall of complete memories to...

MRI provides a sensitive and specific imaging tool to detect acute ischemic stroke by means of a reduced diffusion coefficient of brain water. In a rat model of ischemic stroke, differences in quantitative T1and T2MRI relaxation times (qT1and qT2) between the ischemic lesion (delineated by low diffusion) and the contralateral non-ischemic hemispher...

Background: Objective timing of stroke in emergency departments is expected to improve patient stratification. Magnetic resonance imaging (MRI) relaxations times, T2 and T1ρ , in abnormal diffusion delineated ischaemic tissue were used as proxies of stroke time in a rat model. Methods: Both 'non-ischaemic reference'-dependent and -independent es...

Magnetic resonance imaging (MRI) provides an excellent means of studying tissue microstructure noninvasively since the microscopic tissue environment is imprinted on the MRI signal even at macroscopic voxel level. Mesoscopic variations in magnetic field, created by microstructure, influence the transverse relaxation time (T2) in an orientation-depe...

Many ischaemic stroke patients are ineligible for thrombolytic therapy due to unknown onset time. Quantitative MRI (qMRI) is a potential surrogate for stroke timing. Rats were subjected to permanent middle cerebral artery occlusion and qMRI parameters including hemispheric differences in apparent diffusion coefficient, T2-weighted signal intensitie...

Supplementary data

In MRI, the coherence lifetime T2 is sensitive to the magnetic environment imposed by tissue microstructure and biochemistry in vivo. Here we explore the possibility that the use of T2 relaxometry may provide information complementary to that provided by diffusion tensor imaging (DTI) in ageing of healthy controls (HC), Alzheimer's disease (AD) and...

Objective: The objective of this study was to examine age-dependent changes in both T1-weighted and T2-weighted image contrasts and spin-echo T2 relaxation time in the human brain during healthy ageing. Methods: A total of 37 participants between the ages of 49 and 87 years old were scanned with a 3 Tesla system, using T1-weighted, T2 weighted a...

Recent pharmaceutical trials have demonstrated that slowing or reversing pathology in Alzheimer’s disease is likely to be possible only in the earliest stages of disease, perhaps even before significant symptoms develop. Pathology in Alzheimer’s disease accumulates for well over a decade before symptoms are detected giving a large potential window...

In NMR or MRI of complex materials, including biological tissues and porous materials, magnetic susceptibility differences within the material result in local magnetic field inhomogeneities, even if the applied magnetic field is homogeneous. Mobile nuclear spins move though the inhomogeneous field, by translational diffusion and other mechanisms, r...

Background: Quantitative T2 relaxation magnetic resonance imaging allows estimation of stroke onset time. Aims: We aimed to examine the accuracy of quantitative T1 and quantitative T2 relaxation times alone and in combination to provide estimates of stroke onset time in a rat model of permanent focal cerebral ischemia and map the spatial distrib...

The objective of this study is to present a mathematical model which can describe the spatiotemporal progression of cerebral ischaemia and predict magnetic resonance observables including the apparent diffusion coefficient (ADC) of water and transverse relaxation time T2. This is motivated by the sensitivity of the ADC to the location of cerebral i...

BACKGROUND: The use of T2 relaxation contrast, as measured by MRI, is particularly commonplace in non-invasive assessment of the brain. However, the mechanisms and uses of T2 relaxation in the brain are still not fully understood. The hypothesis that T2 relaxation may show anisotropy in the human brain was studied at 3 T. T2 anisotropy refers to th...

One in four ischaemic stroke patients are ineligible for thrombolytic treatment due to unknown onset time. Quantification of absolute MR relaxation times and signal intensities are potential methods for estimating stroke duration. We compared the accuracy of these approaches and determined whether changes in relaxation times and signal intensities...

Using a set of six 1H-detected triple-resonance NMR experiments, we establish a method for sequence-specific backbone resonance assignment of magic angle spinning (MAS) nuclear magnetic resonance (NMR) spectra of 5-30 kDa proteins. The approach relies on perdeuteration, amide 2H/1H exchange, high magnetic fields, high-spinning frequencies (ωr/2π≥60...

We present two sequences which combine ((1) H,(15) N) and ((15) N,(13) C) selective cross-polarization steps with an efficient variant of the J-based homonuclear transfer scheme, in which a spin-state-selective (S(3) E) block is incorporated to improve both resolution and sensitivity in the direct (13) C dimension. We propose these two sequences as...

Metal ions are ubiquitous in biochemical and cellular processes. Since many metal ions are paramagnetic due to the presence of unpaired electrons, paramagnetic molecules are an important class of targets for research in structural biology and related fields. Today, NMR spectroscopy plays a central role in the investigation of the structure and chem...

Narrow (1) H NMR linewidths can be obtained for fully protonated protein samples in the solid state by using ultrafast magic-angle spinning (60 kHz). Medium-size microcrystalline and noncrystalline proteins can be analyzed without any need for deuteration of the protein sample. This approach provides assignments of the backbone (1) H, (15) N, (13)...

Schmale 1 H‐NMR‐Linien werden mithilfe von schneller Drehung im magischen Winkel (60 kHz) für vollständig protonierte Proteinproben im festen Zustand erhalten. Die Analyse mittelgroßer mikrokristalliner und nichtkristalliner Proteine gelingt ohne Deuterierung der Probe. Dieser Ansatz ermöglicht die Zuordnung der 1H‐, 15N‐, 13Cα‐ und 13CO‐Resonanzen...

Pseudocontact shifts (PCSs) arise in paramagnetic systems in which the susceptibility tensor is anisotropic. PCSs depend upon the distance from the paramagnetic center and the position relative to the susceptibility tensor, and they can be used as structural restraints in protein structure determination. We show that the use of (1)H-detected solid-...

We introduce a new approach to improve structural and dynamical determination of large metalloproteins using solid-state nuclear magnetic resonance (NMR) with (1)H detection under ultrafast magic angle spinning (MAS). The approach is based on the rapid and sensitive acquisition of an extensive set of (15)N and (13)C nuclear relaxation rates. The sy...

A double-zero quantum (DZQ)-refocused INADEQUATE experiment is introduced for J-based NMR correlations under ultra-fast (60 kHz) magic angle spinning (MAS). The experiment records two spectra in the same dataset, a double quantum-single quantum (DQ-SQ) and zero quantum-single quantum (ZQ-SQ) spectrum, whereby the corresponding signals appear at dif...

Paramagnetic phenomena arise due to the presence of one or more unpaired electrons in a system. In this article, we shall be concerned with the effects of unpaired electrons upon nuclear spins in biological systems and the resultant effects upon the NMR spectra in the solid state. In particular, the effects of paramagnetic ions upon proteins studie...

Re-protonation is key: A combination of a high magnetic field (1 GHz) and ultra-fast magic-angle spinning (60 kHz) allows easy detection of NMR spectra revealing details of secondary and tertiary structures of medium-sized proteins. The technique was applied to the 153-residue microcrystalline Zn II-loaded superoxide dismutase (ZnII-SOD) fully [ 2H...