Andreas Glatz

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.

Differentiation of calcified regions and iron deposits in the ageing brain on conventional structural MR images

In the human brain, minerals such as iron and calcium accumulate increasingly with age. They typically appear hypointense on T2*‐weighted MRI sequences. This study aims to explore the differentiation and association between calcified regions and noncalcified iron deposits on clinical brain MRI in elderly, otherwise healthy subjects.

Characterization of multifocal T2*-weighted MRI hypointensities in the basal ganglia of elderly, community-dwelling subjects☆

Multifocal T2*-weighted (T2*w) hypointensities in the basal ganglia, which are believed to arise predominantly from mineralized small vessels and perivascular spaces, have been proposed as a biomarker for cerebral small vessel disease. This study provides baseline data on their appearance on conventional structural MRI for improving and automating current manual segmentation methods. Using a published thresholding method, multifocal T2*w hypointensities were manually segmented from whole brain T2*w volumes acquired from 98 community-dwelling subjects in their early 70s. Connected component analysis was used to derive the average T2*w hypointensity count and load per basal ganglia nucleus, as well as the morphology of their connected components, while nonlinear spatial probability mapping yielded their spatial distribution. T1-weighted (T1w), T2-weighted (T2w) and T2*w intensity distributions of basal ganglia T2*w hypointensities and their appearance on T1w and T2w MRI were investigated to gain further insights into the underlying tissue composition. In 75/98 subjects, on average, 3 T2*w hypointensities with a median total volume per intracranial volume of 50.3 ppm were located in and around the globus pallidus. Individual hypointensities appeared smooth and spherical with a median volume of 12 mm3 and median in-plane area of 4 mm2. Spatial probability maps suggested an association between T2*w hypointensities and the point of entry of lenticulostriate arterioles into the brain parenchyma. T1w and T2w and especially the T2*w intensity distributions of these hypointensities, which were negatively skewed, were generally not normally distributed indicating an underlying inhomogeneous tissue structure. Globus pallidus T2*w hypointensities tended to appear hypo- and isointense on T1w and T2w MRI, whereas those from other structures appeared iso- and hypointense. This pattern could be explained by an increased mineralization of the globus pallidus. In conclusion, the characteristic spatial distribution and appearance of multifocal basal ganglia T2*w hypointensities in our elderly cohort on structural MRI appear to support the suggested association with mineralized proximal lenticulostriate arterioles and perivascular spaces.

Do white matter hyperintensities mediate the association between brain iron deposition and cognitive abilities in older people

Several studies have reported associations between brain iron deposits (IDs), white matter hyperintensities (WMHs) and cognitive ability in older individuals. Whether the association between brain IDs and cognitive abilities in older people is mediated by or independent of total brain tissue damage represented by WMHs visible on structural magnetic resonance imaging (MRI) was examined.

Automated segmentation of multifocal basal ganglia T2*-weighted MRI hypointensities

Multifocal basal ganglia T2*-weighted (T2*w) hypointensities, which are believed to arise mainly from vascular mineralization, were recently proposed as a novel MRI biomarker for small vessel disease and ageing. These T2*w hypointensities are typically segmented semi-automatically, which is time consuming, associated with a high intra-rater variability and low inter-rater agreement. To address these limitations, we developed a fully automated, unsupervised segmentation method for basal ganglia T2*w hypointensities. This method requires conventional, co-registered T2*w and T1-weighted (T1w) volumes, as well as region-of-interest (ROI) masks for the basal ganglia and adjacent internal capsule generated automatically from T1w MRI. The basal ganglia T2*w hypointensities were then segmented with thresholds derived with an adaptive outlier detection method from respective bivariate T2*w/T1w intensity distributions in each ROI. Artefacts were reduced by filtering connected components in the initial masks based on their standardised T2*w intensity variance. The segmentation method was validated using a custom-built phantom containing mineral deposit models, i.e. gel beads doped with 3 different contrast agents in 7 different concentrations, as well as with MRI data from 98 community-dwelling older subjects in their seventies with a wide range of basal ganglia T2*w hypointensities. The method produced basal ganglia T2*w hypointensity masks that were in substantial volumetric and spatial agreement with those generated by an experienced rater (Jaccard index = 0.62 ± 0.40). These promising results suggest that this method may have use in automatic segmentation of basal ganglia T2*w hypointensities in studies of small vessel disease and ageing.

Exploratory analysis of dietary intake and brain iron accumulation detected using magnetic resonance imaging in older individuals : the Lothian Birth cohort 1936

ContextBrain Iron Deposits (IDs) are associated with neurodegenerative diseases and impaired cognitive function in later life, but their cause is unknown. Animal studies have found evidence of relationships between dietary iron, calorie and cholesterol intake and brain iron accumulation.ObjectivesTo investigate the relationship between iron, calorie, and cholesterol intake, blood indicators of iron status, and brain IDs in humans.Design, Setting and ParticipantsCohort of 1063 community-dwelling older individuals born in 1936 (mean age 72.7years, SD=0.7) with dietary information, results from blood sample analyses and brain imaging data contemporaneously in old age.MeasurementsMagnetic Resonance Imaging was used to assess regional volumes of brain IDs in basal ganglia, brainstem, white matter, thalamus, and cortex/border with the corticomedullary junction, using a fully automatic assessment procedure followed by individual checking/correction where necessary. Haemoglobin, red cell count, haematocrit, mean cell volume, ferritin and transferrin were obtained from blood samples and typical daily intake of iron, calories, and cholesterol were calculated from a validated food-frequency questionnaire.ResultsOverall, 72.8% of the sample that had valid MRI (n=676) had brain IDs. The median total volume of IDs was 40mm3, inter-quartile range (IQR)=196. Basal ganglia IDs (median=35, IQR=159.5 mm3), were found in 70.6% of the sample. IDs in the brainstem were found in 12.9% of the sample, in the cortex in 1.9%, in the white matter in 6.1% and in the thalamus in 1.0%. The median daily intake of calories was 1808.5kcal (IQR=738.5), of cholesterol was 258.5mg (IQR=126.2) and of total iron was 11.7mg (IQR=5). Iron, calorie or cholesterol intake were not directly associated with brain IDs. However, caloric intake was associated with ferritin, an iron storage protein (p=0.01).ConclusionOur results suggest that overall caloric, iron and cholesterol intake are not associated with IDs in brains of healthy older individuals but caloric intake could be associated with iron storage. Further work is required to corroborate our findings on other samples and investigate the underlying mechanisms of brain iron accumulation.