David L. Thomas

Measuring Cerebral Blood Flow Using Magnetic Resonance Imaging Techniques

Magnetic resonance imaging techniques measuring CBF have developed rapidly in the last decade, resulting in a wide range of available methods. The most successful approaches are based either on dynamic tracking of a bolus of a paramagnetic contrast agent (dynamic susceptibility contrast) or on arterial spin labeling. This review discusses their principles, possible pitfalls, and potential for absolute quantification and outlines clinical and neuroscientific applications.

In vivo imaging of glucose uptake and metabolism in tumors

Tumors have a greater reliance on anaerobic glycolysis for energy production than normal tissues. We developed a noninvasive method for imaging glucose uptake in vivo that is based on magnetic resonance imaging and allows the uptake of unlabeled glucose to be measured through the chemical exchange of protons between hydroxyl groups and water. This method differs from existing molecular imaging methods because it permits detection of the delivery and uptake of a metabolically active compound in physiological quantities. We show that our technique, named glucose chemical exchange saturation transfer (glucoCEST), is sensitive to tumor glucose accumulation in colorectal tumor models and can distinguish tumor types with differing metabolic characteristics and pathophysiologies. The results of this study suggest that glucoCEST has potential as a useful and cost-effective method for characterizing disease and assessing response to therapy in the clinic.

Global control of hepatitis C: where challenge meets opportunity

We are entering an important new chapter in the story of hepatitis C virus (HCV) infection. There are clear challenges and opportunities. On the one hand, new HCV infections are still occurring, and an estimated 185 million people are or have previously been infected worldwide. Most HCV-infected persons are unaware of their status yet are at risk for life-threatening diseases such as cirrhosis and hepatocellular carcinoma (HCC), whose incidences are predicted to rise in the coming decade. On the other hand, new HCV infections can be prevented, and those that have already occurred can be detected and treated—viral eradication is even possible. How the story ends will largely be determined by the extent to which these rapidly advancing opportunities overcome the growing challenges and by the vigor of the public health response.

Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study: a cross-sectional analysis

BACKGROUND Frontotemporal dementia is a highly heritable neurodegenerative disorder. In about a third of patients, the disease is caused by autosomal dominant genetic mutations usually in one of three genes: progranulin (GRN), microtubule-associated protein tau (MAPT), or chromosome 9 open reading frame 72 (C9orf72). Findings from studies of other genetic dementias have shown neuroimaging and cognitive changes before symptoms onset, and we aimed to identify whether such changes could be shown in frontotemporal dementia. METHODS We recruited participants to this multicentre study who either were known carriers of a pathogenic mutation in GRN, MAPT, or C9orf72, or were at risk of carrying a mutation because a first-degree relative was a known symptomatic carrier. We calculated time to expected onset as the difference between age at assessment and mean age at onset within the family. Participants underwent a standardised clinical assessment and neuropsychological battery. We did MRI and generated cortical and subcortical volumes using a parcellation of the volumetric T1-weighted scan. We used linear mixed-effects models to examine whether the association of neuropsychology and imaging measures with time to expected onset of symptoms differed between mutation carriers and non-carriers. FINDINGS Between Jan 30, 2012, and Sept 15, 2013, we recruited participants from 11 research sites in the UK, Italy, the Netherlands, Sweden, and Canada. We analysed data from 220 participants: 118 mutation carriers (40 symptomatic and 78 asymptomatic) and 102 non-carriers. For neuropsychology measures, we noted the earliest significant differences between mutation carriers and non-carriers 5 years before expected onset, when differences were significant for all measures except for tests of immediate recall and verbal fluency. We noted the largest Z score differences between carriers and non-carriers 5 years before expected onset in tests of naming (Boston Naming Test -0·7; SE 0·3) and executive function (Trail Making Test Part B, Digit Span backwards, and Digit Symbol Task, all -0·5, SE 0·2). For imaging measures, we noted differences earliest for the insula (at 10 years before expected symptom onset, mean volume as a percentage of total intracranial volume was 0·80% in mutation carriers and 0·84% in non-carriers; difference -0·04, SE 0·02) followed by the temporal lobe (at 10 years before expected symptom onset, mean volume as a percentage of total intracranial volume 8·1% in mutation carriers and 8·3% in non-carriers; difference -0·2, SE 0·1). INTERPRETATION Structural imaging and cognitive changes can be identified 5-10 years before expected onset of symptoms in asymptomatic adults at risk of genetic frontotemporal dementia. These findings could help to define biomarkers that can stage presymptomatic disease and track disease progression, which will be important for future therapeutic trials. FUNDING Centres of Excellence in Neurodegeneration.

Early changes in water diffusion, perfusion, T1, and T2 during focal cerebral ischemia in the rat studied at 8.5 T †

The time evolution of water diffusion, perfusion, T1, and T2 is investigated at high magnetic field (8.5 T) following permanent middle cerebral artery occlusion in the rat. Cerebral blood flow maps were obtained using arterial spin tagging. Although the quantitative perfusion measurements in ischemic tissue still pose difficulties, the combined perfusion and diffusion data nevertheless distinguish between a “moderately affected area,” with reduced perfusion but normal diffusion; and a “severely affected area,” in which both perfusion and diffusion are significantly reduced. Two novel magnetic resonance imaging observations are reported, namely, a decrease in T2 and an increase in T1, both within the first few minutes of ischemia. The rapid initial decrease in T2 is believed to be associated with an increase in deoxyhemoglobin levels, while the initial increase in T1 may be related to several factors, such as flow effects, an alteration in tissue oxygenation, and changes in water environment. Magn Reson Med 41:479–485, 1999.

The chronic vascular and haemodynamic response after permanent bilateral common carotid occlusion in newborn and adult rats

Vascular growth and redistribution of flow can compensate for arterial occlusion and possibly reduce the effects of hypoperfusion. As yet there is limited information on the age-dependent nature of vasculature remodelling. In this study, we have monitored the vascular and morphologic changes using magnetic resonance imaging and histology in a chronic bilateral common carotid artery occlusion (BCCAO) model in both newborn and adult rats. Acutely, cerebral blood flow (CBF) decreased immediately after BCCAO, producing a state of oligaemic hypoperfusion. At 6 months after BCCAO in both adult and neonatal rats, the CBF had normalised at control values. To investigate the underlying mechanism for the return of CBF to control values, intra- and extracerebral magnetic resonance angiograms (MRAs) were acquired. As expected, signal from the common carotid arteries was present in the sham-operated rats, but was absent in the BCCAO animals. India ink angiograms demonstrated more tortuous basilar arteries in the adult rats post-BCCAO and MRAs demonstrated more extracerebral midline collaterals in the neonatal rats post-BCCAO, indicating different modes of vascular adaptation dependent on the age at onset of the insult. Both groups had collateral vessels arising from the vertebral arteries, and BCCAO was also associated with increased diameter of basilar, posterior cerebral, posterior communicating, internal carotid, middle cerebral and anterior cerebral arteries. Our study suggests that the developing and mature animals exhibit different patterns of vascular remodelling and that the BCCAO hypoperfusion model will be useful for investigating age-dependent vascular events in response to vasoocclusive disease.

The measurement of diffusion and perfusion in biological systems using magnetic resonance imaging

The aim of this review is to describe two recent developments in the use of magnetic resonance imaging (MRI) in the study of biological systems: diffusion and perfusion MRI. Diffusion MRI measures the molecular mobility of water in tissue, while perfusion MRI measures the rate at which blood is delivered to tissue. Therefore, both these techniques measure quantities which have direct physiological relevance. It is shown that diffusion in biological systems is a complex phenomenon, influenced directly by tissue microstructure, and that its measurement can provide a large amount of information about the organization of this structure in normal and diseased tissue. Perfusion reflects the delivery of essential nutrients to tissue, and so is directly related to its status. The concepts behind the techniques are explained, and the theoretical models that are used to convert MRI data to quantitative physical parameters are outlined. Examples of current applications of diffusion and perfusion MRI are given. In particular, the use of the techniques to study the pathophysiology of cerebral ischaemia/stroke is described. It is hoped that the biophysical insights provided by this approach will help to define the mechanisms of cell damage and allow evaluation of therapies aimed at reducing this damage.

Implementation of quantitative FAIR perfusion imaging with a short repetition time in time‐course studies

Flow‐sensitive alternating inversion recovery (FAIR) is a pulsed arterial spin labeling magnetic resonance imaging method for perfusion quantification. In its standard implementation for quantification with full longitudinal relaxation between acquisitions, its use in time‐course investigations of rapidly changing flow values is limited. The time efficiency can be improved by decreasing the repetition time but quantification becomes problematic. This situation is further complicated if a whole‐body radiofrequency transmit coil is not used since fresh blood spins will flow in from outside the coil. To alleviate these problems, the use of global pre‐saturation is proposed. The resulting expression for the flow signal depends on the relationship between the imaging parameters and the coil inflow time and can be significantly simplified under certain combinations of these parameters. With this implementation of FAIR, quantitative flow maps of gerbil brains were obtained with a 3 minute time resolution in a study of the effects of reperfusion. The pre‐occlusion flow measurements were in good agreement with values obtained by the standard FAIR implementation and by other techniques, but the low values following occlusion were underestimated due to the increased transit times. Magn Reson Med 41:829–840, 1999.

Neuroprotective effects of virally delivered HSPs in experimental stroke.

Heat shock proteins (HSPs) are molecular chaperones with essential roles in modulating the proteolytic machinery and accelerating cell repair. Heat shock protein overexpression has been observed in vivo and in vitro under stresses including heat, nutrient deprivation and ischemia. Experiments in in vivo models of stroke indicate that transgenically overexpressed or virally delivered HSPs can enhance cell survival, but cannot always reduce lesion size. This study aims to assess the effects of virally delivered HSPs in a rat middle cerebral artery occlusion model of reversible focal cerebral ischemia using noninvasive magnetic resonance imaging. Attenuated herpes simplex virus carrying HSP27, HSP70, or a LacZ control was microinjected into the striatum 3 days before ischemia. Multislice T2-weighted images at 24 h after ischemia indicated that lesion volume was reduced by 44% in HSP27-treated animals compared with controls (P 0.019). No significant differences were found between HSP70-treated and control animals (P 0.88). Immunohistochemistry and Western blots revealed that HSP27 and HSP70 expression levels were equally high in injected hemispheres, but only the former had an effect on lesion size. This is the first evidence of the efficacy of gene therapy with any viral vector expressing HSP27 in an experimental model of stroke.

High-resolution fast spin echo imaging of the human brain at 4.7 T: Implementation and sequence characteristics

In this work, a number of important issues associated with fast spin echo (FSE) imaging of the human brain at 4.7 T are addressed. It is shown that FSE enables the acquisition of images with high resolution and good tissue contrast throughout the brain at high field strength. By employing an echo spacing (ES) of 22 ms, one can use large flip angle refocusing pulses (162°) and a low acquisition bandwidth (50 kHz) to maximize the signal‐to‐noise ratio (SNR). A new method of phase encode (PE) ordering (called “feathering”) designed to reduce image artifacts is described, and the contributions of RF (B1) inhomogeneity, different echo coherence pathways, and magnetization transfer (MT) to FSE signal intensity and contrast are investigated. B1 inhomogeneity is measured and its effect is shown to be relatively minor for high‐field FSE, due to the self‐compensating characteristics of the sequence. Thirty‐four slice data sets (slice thickness = 2 mm; in‐plane resolution = 0.469 mm; acquisition time = 11 min 20 s) from normal volunteers are presented, which allow visualization of brain anatomy in fine detail. This study demonstrates that high‐field FSE produces images of the human brain with high spatial resolution, SNR, and tissue contrast, within currently prescribed power deposition guidelines. Magn Reson Med 51:1254–1264, 2004.