Respiratory challenge MRI: practical aspects

Respiratory challenge MRI is the modification of arterial oxygen (PaO2) and/or carbon dioxide (PaCO2) concentration to induce a change in cerebral function or metabolism which is then measured by MRI. Alterations in arterial gas concentrations can lead to profound changes in cerebral haemodynamics which can be studied using a variety of MRI sequences. Whilst such experiments may provide a wealth of information, conducting them can be complex and challenging. In this paper we review the rationale for respiratory challenge MRI including the effects of oxygen and carbon dioxide on the cerebral circulation. We also discuss the planning, equipment, monitoring and techniques that have been used to undertake these experiments. We finally propose some recommendations in this evolving area for conducting these experiments to enhance data quality and comparison between techniques

A neuroradiologist's guide to arterial spin labeling MRI in clinical practice

Arterial spin labeling (ASL) is a non-invasive MRI technique to measure cerebral blood flow (CBF). This review provides a practical guide and overview of the clinical applications of ASL of the brain, as well its potential pitfalls. The technical and physiological background is also addressed. At present, main areas of interest are cerebrovascular disease, dementia and neuro-oncology. In cerebrovascular disease, ASL is of particular interest owing to its quantitative nature and its capability to determine cerebral arterial territories. In acute stroke, the source of the collateral blood supply in the penumbra may be visualised. In chronic cerebrovascular disease, the extent and severity of compromised cerebral perfusion can be visualised, which may be used to guide therapeutic or preventative intervention. ASL has potential for the detection and follow-up of arteriovenous malformations. In the workup of dementia patients, ASL is proposed as a diagnostic alternative to PET. It can easily be added to the routinely performed structural MRI examination. In patients with established Alzheimer's disease and frontotemporal dementia, hypoperfusion patterns are seen that are similar to hypometabolism patterns seen with PET. Studies on ASL in brain tumour imaging indicate a high correlation between areas of increased CBF as measured with ASL and increased cerebral blood volume as measured with dynamic susceptibility contrast-enhanced perfusion imaging. Major advantages of ASL for brain tumour imaging are the fact that CBF measurements are not influenced by breakdown of the blood-brain barrier, as well as its quantitative nature, facilitating multicentre and longitudinal studies

Reversal of neurovascular coupling in the default mode network: evidence from hypoxia

Local changes in cerebral blood flow are thought to match changes in neuronal activity, a phenomenon termed neurovascular coupling. Hypoxia increases global resting cerebral blood flow, but regional cerebral blood flow (rCBF) changes are non-uniform. Hypoxia decreases baseline rCBF to the default mode network (DMN), which could reflect either decreased neuronal activity or altered neurovascular coupling. To distinguish between these hypotheses, we characterized the effects of hypoxia on baseline rCBF, task performance, and the hemodynamic (BOLD) response to task activity. During hypoxia, baseline CBF increased across most of the brain, but decreased in DMN regions. Performance on memory recall and motion detection tasks was not diminished, suggesting task-relevant neuronal activity was unaffected. Hypoxia reversed both positive and negative task-evoked BOLD responses in the DMN, suggesting hypoxia reverses neurovascular coupling in the DMN of healthy adults. The reversal of the BOLD response was specific to the DMN. Hypoxia produced modest increases in activations in the visual attention network (VAN) during the motion detection task, and had no effect on activations in the visual cortex during visual stimulation. This regional specificity may be particularly pertinent to clinical populations characterized by hypoxemia and may enhance understanding of regional specificity in neurodegenerative disease pathology

The use of hypercapnic challenge blood oxygen level dependent (BOLD) MRI for the investigation of childhood steno-occlusive arteriopathy

BACKGROUND: In childhood, cerebral arteriopathy causes cerebral ischaemia and infarction via two related mechanisms. The first, thrombotic vaso-occlusive stroke is the more typical mechanism of stroke in childhood. The second mechanism of infarction related to arteriopathy and not seen in other forms of ischaemic stroke is that of chronic hypoperfusion of the brain. The infarcts in this case are typically located in watershed zones and can accumulate gradually over time. Moyamoya is the prototypic arteriopathy representing the hypoperfusion injury. It is characterized by chronic progressive narrowing of the distal internal carotid, proximal middle cerebral and anterior cerebral arteries; chronic low flow infarction with accumulating ‘string of pearls’ in the white matter (Fig 1). It is this chronic hypoperfusion of the brain that is the subject of my PhD thesis. Cerebrovascular reactivity is a marker of cerebrovascular reserve and has been shown to be a biomarker of ischaemic risk in adults. OBJECTIVES: The primary objectives were to, in a group of children with moyamoya: 1) Validate the use of a qualitative measure of cerebrovascular reactivity as a biomarker of ischaemic risk, namely, hypercapnic challenge BOLD MRI CVR (hBOLD CVR) via two methods: a) breath-holding and b) induced hypercapnia during general anaesthesia as reliable and repeatable for use in the paediatric population 2) Assess the utility of qualitative assessment of cerebrovascular reactivity using hBOLD CVR as a tool for the identification of the risk of ischaemia in children with arteriopathy Method Hypercapnic challenge hBOLD CVR studies were obtained in children with steno-occlusive arteriopathy prospectively enrolled in The Hospital for Sick Children Stroke Registry. Semi-quantitative methods of measuring CVR were devised and used for the purpose of analysis. hBOLD CVR studies were analysed for reliability and reproducibility of the method of analysis. Clinical and radiologic data were collected and hBOLD CVR findings described for all children enrolled. Exploratory analysis of hBOLD CVR as a potential biomarker of ischaemic risk in the paediatric population were conducted. In particular association of hBOLD CVR with clinical symptomatology; parenchymal and vascular indicators of arteriopathy; neuropsychological outcome and cortical thickness were examined. Results Forty seven children (37 Bilateral or unilateral Moyamoya arteriopathy, 6 Unilateral Non-moyamoya arteriopathy [Transient Cerebral Arteriopathy] and 4 Bilateral Non-moyamoya arteriopathy [2 PHACE(S), 1 Takayasu arteritis, 1 Sickle Cell Disease]) were enrolled and had hBOLD CVR studies. The mean age of diagnosis of arteriopathy across all groups was 8.1 years (SD 4.2) (range 7 months - 18 years). Clinical and radiographic features differed across arteriopathy groups. Most presented with acute stroke, however, among children with NF1-MM most (almost 50%) were asymptomatic and diagnosed on screening MRIs. Infarction patterns differed, with deep watershed infarction being the typical pattern in the moyamoya group in contrast to thrombotic vaso-occlusive infarction pattern in the Non-moyamoya groups. Qualitative hBOLD CVR abnormalities were concordant with moyamoya laterality, and in unilateral moyamoya demonstrated tissue level microvascular dysfunction in the contralateral unaffected hemisphere. Qualitative hBOLD CVR abnormalities demonstrated concordance with clinically important manifestations of ischaemia including stroke, transient ischaemic attacks, cortical thinning and IQ. There was a lack of concordance with indices of executive function. In addition the moderate to severe steno-occlusive arteriopathy seen in the children with Transient Cerebral Arteriopathy was not associated with abnormality of hBOLD CVR. Conclusion The thesis studies demonstrated that qualitative assessment of hBOLD CVR using breath-hold or general anaesthetic is feasible, reproducible and reliable in paediatric population. The utility of hBOLD CVR as a measure of tissue level microvascular dysfunction and thus a biomarker of ischaemic risk was demonstrated. However, larger longitudinal studies are required to characterize this further

Is High Blood Pressure Self-Protection for the Brain?

Rationale: Data from animal models of hypertension indicate that high blood pressure may develop as a vital mechanism to maintain adequate blood flow to the brain. We propose that congenital vascular abnormalities of the posterior cerebral circulation and cerebral hypoperfusion could partially explain the etiology of essential hypertension, which remains enigmatic in 95% of patients. Objective: To evaluate the role of the cerebral circulation in the pathophysiology of hypertension. Methods and Results: We completed a series of retrospective and mechanistic case-control magnetic resonance imaging and physiological studies, in normotensive and hypertensive humans (n=259). Interestingly, in humans with hypertension, we report a higher prevalence of congenital cerebrovascular variants; vertebral artery hypoplasia and an incomplete posterior circle of Willis, which were coupled with increased cerebral vascular resistance, reduced cerebral blood flow and a higher incidence of lacunar type infarcts. Causally, cerebral vascular resistance was elevated before the onset of hypertension and elevated sympathetic nerve activity (n=126). Interestingly, untreated hypertensive patients (n=20) had a cerebral blood flow similar to age-matched controls (n=28). However, participants receiving anti-hypertensive therapy (with blood pressure controlled below target levels) had reduced cerebral perfusion (n=19). Finally, elevated cerebral vascular resistance was a predictor of hypertension suggesting it may be a novel prognostic and/or diagnostic marker (n=126). < Conclusions: Our data indicate that congenital cerebrovascular variants in the posterior circulation and the associated cerebral hypoperfusion may be a factor in triggering hypertension. Therefore lowering blood pressure may worsen cerebral perfusion in susceptible individuals

Optimisation, evaluation and application of cerebrovascular reactivity measurement using magnetic resonance imaging in patients with cerebral small vessel disease

Small vessel disease (SVD) is a common cause of strokes and dementia. Currently, there are no treatments; therefore, developing and validating early biomarkers of disease progression and treatment response is important for future drug trials. Though SVD pathogenesis is not well understood, findings from previous studies suggest that blood-brain barrier dysfunction and impaired cerebrovascular reactivity (CVR) contribute to the disease. The latter can be measured in vivo using a vasoactive stimulus in parallel with magnetic resonance imaging (MRI) techniques sensitive to blood flow, such as blood oxygen level dependent (BOLD) contrast, and has frequently been assessed in patients with steno-occlusive diseases. However, it is unclear if the technique is reliable when investigating cerebrovascular health in deep structures of the brain where SVD is prevalent. Therefore, this thesis aimed to assess and optimise the reliability of CVR measurements and deepen our understanding of its role in SVD pathogenesis. A systematic review was performed to provide a detailed overview of CVR MRI methodologies and clinical applications, including SVD, present in the literature, which identified several acquisition and analysis methods, a need for greater standardisation and lack of data on reliability. Specifically in SVD research, there was limited application of CVR MRI in SVD populations, little optimisation and reliability assessment of CVR in deep brain structures relevant to SVD, such as in white and subcortical grey matter. Following those findings, the effects of voxel- and region-based analysis approaches on reliability of CVR estimates were investigated using simulations and test-retest data from healthy volunteers. Voxel-based CVR magnitude estimates in tissues with high noise levels were prone to bias, whereas biases in region-based estimates were independent of noise level, but consistently underestimated CVR magnitude relative to the ground-truth mean. Furthermore, the test-retest study confirmed the repeatability of CVR estimates from a BOLD-CVR experiment with fixed inhaled stimulus, although a systematic, but small, bias was detected due to habituation to the gas challenge. The data from healthy volunteers were further used to conduct a proof-of-concept and investigate the feasibility of extracting cerebral pulsatility from BOLD-CVR data. Small-to-moderate correlations with pulsatility from phase-contrast MRI were found depending on the regions considered. CVR pulsatility was also computed in a small cohort of SVD patients: it was higher than in healthy volunteers, but no associations were found with SVD burden. It was concluded that further optimisation and validation of the technique is needed before being suitable for clinical research. Following the optimisation of the CVR MRI technique, relationships between CVR and SVD neuroimaging features, cognition, stroke severity and outcome were investigated cross-sectionally and longitudinally in a cohort of patients with mild stroke. In the cross-sectional analysis, CVR impairment in normal-appearing and damaged tissues was associated with worse SVD burden and cognition deficit. Furthermore, the longitudinal analysis showed that baseline CVR impairment predicted worsening of white matter hyperintensity and perivascular space volumes after one year. In conclusion, assessment of CVR in the brain and its deeper structures was successfully conducted in healthy volunteers and patients with SVD using MRI. However, this required appropriate optimisation of processing strategy as the latter can affect accuracy of CVR parameters and inter-study comparability. Importantly, applying the technique in a cohort of SVD patients led to the findings that CVR impairment was related to worse SVD burden and is a potential marker of SVD severity and progression

The pathophysiology of CADASIL: studies in a Scottish cohort

Since identification that mutations in NOTCH3 are responsible for cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) in the early 1990s, there has been extensive characterisation of the clinical and radiological features of the disease. However therapeutic interventions remain elusive, partly due to a limited understanding of the vascular pathophysiology and how it leads to the development of strokes, cognitive decline and disability. The apparent rarity and heterogenous natural history of CADASIL potentially make conducting any longitudinal or therapeutic trials difficult. The role of disease biomarkers is therefore of some interest. This thesis focuses on vascular function in CADASIL and how it may relate to clinical and radiological markers of disease. Establishing the prevalence of CADASIL in the West of Scotland was important to assess the impact of the disease, and how feasible a trial would be. A mutation prevalence of 10.7 per 100,000 was demonstrated, suggesting significant under diagnosis of the disease across much of Scotland. Cerebral hypoperfusion is thought to be important in CADASIL, and it has been shown that vascular abnormalities precede the development of brain pathology in mouse models. Investigation of vascular function in patients, both in the brain and systemically, requires less invasive measures. Arterial spin labelling magnetic resonance imaging (MRI) and transcranial Doppler ultrasound (TCD) can both be used to obtain non-invasive and quantifiable indices of vascular function. Monitoring patients with MRI whilst they receive different concentrations of inspired oxygen and carbon dioxide can provide information on brain function, and I reviewed the practicalities of this technique in order to guide the design of the studies in this thesis. 22 CADASIL patients were recruited to a longitudinal study. Testing included peripheral vascular assessment, assessment of disability, neurological dysfunction, mood and cognition. A CO2 reactivity challenge during both TCD and arterial spin labelling MRI, and detailed MRI sequences were obtained. I was able to demonstrate that vasoreactivity was associated with the number of lacunes and brain atrophy, as were carotid intima-media thickness, vessel stiffness, and age. Patients with greater disability, higher depressive symptoms and poorer processing speed showed a tendency to worse cerebral vasoreactivity but numbers were small. This observation suggests vasoreactivity may have potential as a therapeutic target, or a biomarker. I then wished to establish if arterial spin labelling MRI was useful for assessing change in cerebral blood flow in CADASIL patients. Cortical grey matter showed the highest blood flow, mean (SD), 55 (10) ml/100g/min and blood flow was significantly lower within hyperintensities (19 (4) ml/100g/min; p <0.001). Over one year, blood flow in both grey matter (mean -7 (10) %; p = 0.028) and deep white matter (-8 (13) %; p = 0.036) declined significantly. Cerebrovascular reactivity did not change over one year. I then investigated whether baseline vascular markers were able to predict change in radiological or neuropsychological measures of disease. Changes in brain volume, lacunes, microbleeds and normalised subcortical hyperintensity volume (increase of 0.8%) were shown over one year. Baseline vascular parameters were not able to predict these changes, or those in neuropsychological testing. NOTCH3 is found throughout the body and a systemic vasculopathy has been seen particularly affecting resistance vessels. Gluteal biopsies were obtained from 20 CADASIL patients, and ex vivo myography investigated the response to vasoactive agents. Evidence of impairment in both vasodilation and vasoconstriction was shown. The addition of antioxidants improved endothelium-dependent relaxation, indicating a role for oxidative stress in CADASIL pathology. Myography measures were not related to in vivo measures in the sub-group of patients who had taken part in both studies. The small vessels affected in CADASIL are unable to be imaged by conventional MR imaging so I aimed to establish which vessels might be responsible for lacunes with use of a microangiographic template overlaid onto brain images registered to a standard brain template. This showed most lacunes are small and associated with tertiary arterioles. On the basis of this thesis, it is concluded that vascular dysfunction plays an important role in the pathophysiology of CADASIL, and further assessment of vascular measures in longitudinal studies is needed. Arterial spin labelling MRI should be used as it is a reliable, non-invasive modality that can measure change over one year. Furthermore conventional cardiovascular risk factor prevention should be undertaken in CADASIL patients to delay the deleterious effects of the disease

Diffuse optical monitoring of cerebral hemodynamics in experimental and clinical neurology

The study of the brain using diffuse optical methods has progressed rapidly in the recent years. The possibility of studying the cerebral microvasculature in addition to the portability and low cost of these devices, opens a new door in the study of the cerebral pathophysiologies. In this scenario, the study of the cerebral hemodynamics of ischemic patients might allow neurologists to improve the performance of the early medical treatments and therapies used up to date. In this thesis, I have conducted a pioneering study where cerebral autoregulation was studied in ischemic stroke patients during the early hours after the stroke. Similarly, some other diseases can provoke impaired cerebral autoregulation in the long term. One of them is the obstructive sleep apnoea (OSA) syndrome which can provoke a risk increase of developing cardiovascular diseases and ischemic stroke. In this regards, I have carried out the largest to date study conducted with Diffuse Correlation Spectroscopy in patients with OSA and I have compared their hemodynamical response to an orthostatic challenge test with a control group of healthy subjects. Finally, primary animal research is of great importance in the development of new therapies, medical strategies and in the validation of new drugs with the aim of reducing the high mortality and slow and costly recovery of ischemic patients. In consequence, many models of ischemia are reproduced in rodents where the cerebral hemodynamics are studied using expensive equipments such as MRI scanners or by techniques that involve invasive approaches like for instance removing the scalp or thinning the skull which in turn cause a worsening in the living conditions of the animal. In relation to this point, I have developed a fully non-invasive method to study the cerebral hemodynamics in rats that allows to proceed with longitudinal studies and which I hope will be useful in future biomedical research.El estudio del cerebro mediante métodos de óptica difusa ha progresado rápidamente en los últimos años. La posibilidad de estudiar la microvasculatura cerebral junto con la portabilidad y bajo coste de estos equipos abre una ventana de posibilidades para el estudio de fisiopatologías cerebrales. En este escenario, el estudio de la hemodinámica cerebral en pacientes isquémicos podría permitir a los neurólogos mejorar el rendimiento de los tratamientos médicos tempranos y de las terapias utilizadas hasta la fecha. En esta tesis he realizado un estudio pionero al respecto, estudiando por primera vez la hemodinámica cerebral de pacientes isquémicos durante las primeras horas después del infarto cerebral. De igual manera, existen otro tipo de enfermedades que pueden desarrollar un empeoramiento a largo plazo de la autorregulación cerebral. Entre ellas destaca el síndrome de apnea obstructivo (SAO), debido al cual el empeoramiento de la hemodinámica cerebral provoca un aumento del riesgo directo de sufrir enfermedades cardiovasculares y un aumento del riesgo de infarto cerebral. Al respecto, he llevado a cabo el mayor estudio hasta la fecha con pacientes con SAO donde he estudiado su respuesta hemodinámica a un test ortostático comparado estos resultados con los obtenidos en grupo de control de pacientes sanos. Finalmente, la investigación primaria en animales es de vital importancia en el desarrollo de nuevas terapias y estrategias médicas así como en la validación de nuevos fármacos que reduzcan la alta mortalidad y la lenta y costosa recuperación de los pacientes isquémicos. En consecuencia, numerosos modelos de isquemia son reproducidos en roedores donde se estudia la hemodinámica cerebral mediante caros equipos como los resonadores magnéticos o mediante técnicas que implican someter al animal a cierta cirugía en la que se le sustrae el cuero cabelludo o se le lima el cráneo. En relación con esto último, he desarrollado un método completamente no invasivo para estudiar la hemodinámica cerebral en ratas y que permite llevar a cabo estudios longitudinales, el cual espero sea utilidad en futuras investigaciones biomédicas