Michael J. Thrippleton

Assessment of blood–brain barrier disruption using dynamic contrast-enhanced MRI. A systematic review

There is increasing recognition of the importance of blood–brain barrier (BBB) disruption in aging, dementia, stroke and multiple sclerosis in addition to more commonly-studied pathologies such as tumors. Dynamic contrast-enhanced MRI (DCE-MRI) is a method for studying BBB disruption in vivo. We review pathologies studied, scanning protocols and data analysis procedures to determine the range of available methods and their suitability to different pathologies. We systematically review the existing literature up to February 2014, seeking studies that assessed BBB integrity using T1-weighted DCE-MRI techniques in animals and humans in normal or abnormal brain tissues. The literature search provided 70 studies that were eligible for inclusion, involving 417 animals and 1564 human subjects in total. The pathologies most studied are intracranial neoplasms and acute ischemic strokes. There are large variations in the type of DCE-MRI sequence, the imaging protocols and the contrast agents used. Moreover, studies use a variety of different methods for data analysis, mainly based on model-free measurements and on the Patlak and Tofts models. Consequently, estimated KTrans values varied widely. In conclusion, DCE-MRI is shown to provide valuable information in a large variety of applications, ranging from common applications, such as grading of primary brain tumors, to more recent applications, such as assessment of subtle BBB dysfunction in Alzheimers disease. Further research is required in order to establish consensus-based recommendations for data acquisition and analysis and, hence, improve inter-study comparability and promote wider use of DCE-MRI.

Cerebral blood flow in small vessel disease: a systematic review and meta-analysis

White matter hyperintensities are frequent on neuroimaging of older people and are a key feature of cerebral small vessel disease. They are commonly attributed to chronic hypoperfusion, although whether low cerebral blood flow is cause or effect is unclear. We systematically reviewed studies that assessed cerebral blood flow in small vessel disease patients, performed meta-analysis and sensitivity analysis of potential confounders. Thirty-eight studies (n = 4006) met the inclusion criteria, including four longitudinal and 34 cross-sectional studies. Most cerebral blood flow data were from grey matter. Twenty-four cross-sectional studies (n = 1161) were meta-analysed, showing that cerebral blood flow was lower in subjects with more white matter hyperintensity, globally and in most grey and white matter regions (e.g. mean global cerebral blood flow: standardised mean difference−0.71, 95% CI −1.12, −0.30). These cerebral blood flow differences were attenuated by excluding studies in dementia or that lacked age-matching. Four longitudinal studies (n = 1079) gave differing results, e.g., more baseline white matter hyperintensity predated falling cerebral blood flow (3.9 years, n = 575); cerebral blood flow was low in regions that developed white matter hyperintensity (1.5 years, n = 40). Cerebral blood flow is lower in subjects with more white matter hyperintensity cross-sectionally, but evidence for falling cerebral blood flow predating increasing white matter hyperintensity is conflicting. Future studies should be longitudinal, obtain more white matter data, use better age-correction and stratify by clinical diagnosis.

Integrity of normal-appearing white matter: Influence of age, visible lesion burden and hypertension in patients with small-vessel disease

White matter hyperintensities accumulate with age and occur in patients with stroke, but their pathogenesis is poorly understood. We measured multiple magnetic resonance imaging biomarkers of tissue integrity in normal-appearing white matter and white matter hyperintensities in patients with mild stroke, to improve understanding of white matter hyperintensities origins. We classified white matter into white matter hyperintensities and normal-appearing white matter and measured fractional anisotropy, mean diffusivity, water content (T1-relaxation time) and blood–brain barrier leakage (signal enhancement slope from dynamic contrast-enhanced magnetic resonance imaging). We studied the effects of age, white matter hyperintensities burden (Fazekas score) and vascular risk factors on each biomarker, in normal-appearing white matter and white matter hyperintensities, and performed receiver-operator characteristic curve analysis. Amongst 204 patients (34.3–90.9 years), all biomarkers differed between normal-appearing white matter and white matter hyperintensities (P < 0.001). In normal-appearing white matter and white matter hyperintensities, mean diffusivity and T1 increased with age (P < 0.001), all biomarkers varied with white matter hyperintensities burden (P < 0.001; P = 0.02 signal enhancement slope), but only signal enhancement slope increased with hypertension (P = 0.028). Fractional anisotropy showed complex age-white matter hyperintensities-tissue interactions; enhancement slope showed white matter hyperintensities-tissue interactions. Mean diffusivity distinguished white matter hyperintensities from normal-appearing white matter best at all ages. Blood–brain barrier leakage increases with hypertension and white matter hyperintensities burden at all ages in normal-appearing white matter and white matter hyperintensities, whereas water mobility and content increase as tissue damage accrues, suggesting that blood–brain barrier leakage mediates small vessel disease-related brain damage.

Tracer kinetic modelling for DCE-MRI quantification of subtle blood–brain barrier permeability

There is evidence that subtle breakdown of the blood–brain barrier (BBB) is a pathophysiological component of several diseases, including cerebral small vessel disease and some dementias. Dynamic contrast-enhanced MRI (DCE-MRI) combined with tracer kinetic modelling is widely used for assessing permeability and perfusion in brain tumours and body tissues where contrast agents readily accumulate in the extracellular space. However, in diseases where leakage is subtle, the optimal approach for measuring BBB integrity is likely to differ since the magnitude and rate of enhancement caused by leakage are extremely low; several methods have been reported in the literature, yielding a wide range of parameters even in healthy subjects. We hypothesised that the Patlak model is a suitable approach for measuring low-level BBB permeability with low temporal resolution and high spatial resolution and brain coverage, and that normal levels of scanner instability would influence permeability measurements. DCE-MRI was performed in a cohort of mild stroke patients (n = 201) with a range of cerebral small vessel disease severity. We fitted these data to a set of nested tracer kinetic models, ranking their performance according to the Akaike information criterion. To assess the influence of scanner drift, we scanned 15 healthy volunteers that underwent a “sham” DCE-MRI procedure without administration of contrast agent. Numerical simulations were performed to investigate model validity and the effect of scanner drift. The Patlak model was found to be most appropriate for fitting low-permeability data, and the simulations showed vp and KTrans estimates to be reasonably robust to the model assumptions. However, signal drift (measured at approximately 0.1% per minute and comparable to literature reports in other settings) led to systematic errors in calculated tracer kinetic parameters, particularly at low permeabilities. Our findings justify the growing use of the Patlak model in low-permeability states, which has the potential to provide valuable information regarding BBB integrity in a range of diseases. However, absolute values of the resulting tracer kinetic parameters should be interpreted with extreme caution, and the size and influence of signal drift should be measured where possible.

Rationale, design and methodology of the image analysis protocol for studies of patients with cerebral small vessel disease and mild stroke

Cerebral small vessel disease (SVD) is common in ageing and patients with dementia and stroke. Its manifestations on magnetic resonance imaging (MRI) include white matter hyperintensities, lacunes, microbleeds, perivascular spaces, small subcortical infarcts, and brain atrophy. Many studies focus only on one of these manifestations. A protocol for the differential assessment of all these features is, therefore, needed.

Blood-brain barrier failure as a core mechanism in cerebral small vessel disease and dementia: evidence from a cohort study

Small vessel disease (SVD) is a common contributor to dementia. Subtle blood‐brain barrier (BBB) leakage may be important in SVD‐induced brain damage.

Blood pressure and sodium: Association with MRI markers in cerebral small vessel disease:

Dietary salt intake and hypertension are associated with increased risk of cardiovascular disease including stroke. We aimed to explore the influence of these factors, together with plasma sodium concentration, in cerebral small vessel disease (SVD). In all, 264 patients with nondisabling cortical or lacunar stroke were recruited. Patients were questioned about their salt intake and plasma sodium concentration was measured; brain tissue volume and white-matter hyperintensity (WMH) load were measured using structural magnetic resonance imaging (MRI) while diffusion tensor MRI and dynamic contrast-enhanced MRI were acquired to assess underlying tissue integrity. An index of added salt intake (P = 0.021), pulse pressure (P = 0.036), and diagnosis of hypertension (P = 0.0093) were positively associated with increased WMH, while plasma sodium concentration was associated with brain volume (P = 0.019) but not with WMH volume. These results are consistent with previous findings that raised blood pressure is associated with WMH burden and raise the possibility of an independent role for dietary salt in the development of cerebral SVD.

Magnetic Resonance Imaging for Assessment of Cerebrovascular Reactivity in Cerebral Small Vessel Disease. A Systematic Review.

Cerebral small vessel disease (SVD) pathophysiology is poorly understood. Cerebrovascular reactivity (CVR) impairment may play a role, but evidence to date is mainly indirect. Magnetic resonance imaging (MRI) allows investigation of CVR directly in the tissues affected by SVD. We systematically reviewed the use of MRI to measure CVR in subjects with SVD. Five studies (total n = 155 SVD subjects, 84 controls) provided relevant data. The studies included different types of patients. Each study used blood oxygen level dependent (BOLD) MRI to assess CVR but a different vasoactive stimulus and method of calculating CVR. CVR decreased with increasing white matter hyperintensities in two studies (n = 17, 11%) and in the presence of microbleeds in another. Three studies (n = 138, 89%) found no association of CVR with white matter hyperintensities. No studies provided tissue-specific CVR values. CVR decreased with age in three studies, and with female gender and increasing diastolic blood pressure in one study. Safety and tolerability data were limited. Larger studies using CVR appear to be feasible and are needed, preferably with more standardized methods, to determine if specific clinical or radiological features of SVD are more or less associated with impaired CVR.

Advanced Neuroimaging of Cerebral Small Vessel Disease.

Opinion statementCerebral small vessel disease (SVD) is characterised by damage to deep grey and white matter structures of the brain and is responsible for a diverse range of clinical problems that include stroke and dementia. In this review, we describe advances in neuroimaging published since January 2015, mainly with magnetic resonance imaging (MRI), that, in general, are improving quantification, observation and investigation of SVD focussing on three areas: quantifying the total SVD burden, imaging brain microstructural integrity and imaging vascular malfunction. Methods to capture ‘whole brain SVD burden’ across the spectrum of SVD imaging changes will be useful for patient stratification in clinical trials, an approach that we are already testing. More sophisticated imaging measures of SVD microstructural damage are allowing the disease to be studied at earlier stages, will help identify specific factors that are important in development of overt SVD imaging features and in understanding why specific clinical consequences may occur. Imaging vascular function will help establish the precise blood vessel and blood flow alterations at early disease stages and, together with microstructural integrity measures, may provide important surrogate endpoints in clinical trials testing new interventions. Better knowledge of SVD pathophysiology will help identify new treatment targets, improve patient stratification and may in future increase efficiency of clinical trials through smaller sample sizes or shorter follow-up periods. However, most of these methods are not yet sufficiently mature to use with confidence in clinical trials, although rapid advances in the field suggest that reliable quantification of SVD lesion burden, tissue microstructural integrity and vascular dysfunction are imminent.

Reliability of MRSI brain temperature mapping at 1.5 and 3 T

MRSI permits the non‐invasive mapping of brain temperature in vivo, but information regarding its reliability is lacking. We obtained MRSI data from 31 healthy male volunteers [age range, 22–40 years; mean ± standard deviation (SD), 30.5 ± 5.0 years]. Eleven subjects (age range, 23–40 years; mean ± SD, 30.5 ± 5.2 years) were invited to receive four point‐resolved spectroscopy MRSI scans on each of 3 days in both 1.5‐T (TR/TE = 1000/144 ms) and 3‐T (TR/TE = 1700/144 ms) clinical scanners; a further 20 subjects (age range, 22–40 years; mean ± SD, 30.5 ± 4.9 years) were scanned on a single occasion at 3 T. Data were fitted in the time domain to determine the water–N‐acetylaspartate chemical shift difference, from which the temperature was estimated. Temperature data were analysed using a linear mixed effects model to determine variance components and systematic temperature changes during the scanning sessions. To characterise the effects of instrumental drift on apparent MRSI brain temperature, a temperature‐controlled phantom was constructed and scanned on multiple occasions. Components of apparent in vivo temperature variability at 1.5 T/3 T caused by inter‐subject (0.18/0.17 °C), inter‐session (0.18/0.15 °C) and within‐session (0.36/0.14 °C) effects, as well as voxel‐to‐voxel variation (0.59/0.54 °C), were determined. There was a brain cooling effect during in vivo MRSI of 0.10 °C [95% confidence interval (CI): –0.110, –0.094 °C; p < 0.001] and 0.051 °C (95% CI: –0.054, –0.048 °C; p < 0.001) per scan at 1.5 T and 3 T, respectively, whereas phantom measurements revealed minimal drift in apparent MRSI temperature relative to fibre‐optic temperature measurements. The mean brain temperature at 3 T was weakly associated with aural (R = 0.55, p = 0.002) and oral (R = 0.62, p < 0.001) measurements of head temperature. In conclusion, the variability associated with MRSI brain temperature mapping was quantified. Repeatability was somewhat higher at 3 T than at 1.5 T, although subtle spatial and temporal variations in apparent temperature were demonstrated at both field strengths. Such data should assist in the efficient design of future clinical studies.