Tom MacGillivray

Retinal vascular image analysis as a potential screening tool for cerebrovascular disease : a rationale based on homology between cerebral and retinal microvasculatures

The retinal and cerebral microvasculatures share many morphological and physiological properties. Assessment of the cerebral microvasculature requires highly specialized and expensive techniques. The potential for using non‐invasive clinical assessment of the retinal microvasculature as a marker of the state of the cerebrovasculature offers clear advantages, owing to the ease with which the retinal vasculature can be directly visualized in vivo and photographed due to its essential two‐dimensional nature. The use of retinal digital image analysis is becoming increasingly common, and offers new techniques to analyse different aspects of retinal vascular topography, including retinal vascular widths, geometrical attributes at vessel bifurcations and vessel tracking. Being predominantly automated and objective, these techniques offer an exciting opportunity to study the potential to identify retinal microvascular abnormalities as markers of cerebrovascular pathology. In this review, we describe the anatomical and physiological homology between the retinal and cerebral microvasculatures. We review the evidence that retinal microvascular changes occur in cerebrovascular disease and review current retinal image analysis tools that may allow us to use different aspects of the retinal microvasculature as potential markers for the state of the cerebral microvasculature.

Abdominal Aortic Aneurysm Growth Predicted by Uptake of Ultrasmall Superparamagnetic Particles of Iron Oxide A Pilot Study

Background— Abdominal aortic aneurysms are a major cause of death. Prediction of aneurysm expansion and rupture is challenging and currently relies on the simple measure of aneurysm diameter. Using MRI, we aimed to assess whether areas of cellular inflammation correlated with the rate of abdominal aortic aneurysm expansion. Methods and Results— Stable patients (n=29; 27 male; age, 70±5 years) with asymptomatic abdominal aortic aneurysms (4.0 to 6.6 cm) were recruited from a surveillance program and imaged using a 3-T MRI scanner before and 24 to 36 hours after administration of ultrasmall superparamagnetic particles of iron oxide (USPIO). The change in T2* value on T2*-weighted imaging was used to detect accumulation of USPIO within the abdominal aortic aneurysm. Histological examination of aneurysm tissue confirmed colocalization and uptake of USPIO in areas with macrophage infiltration. Patients with distinct mural uptake of USPIO had a 3-fold higher growth rate (n=11, 0.66 cm/y; P=0.020) than those with no (n=6, 0.22 cm/y) or nonspecific USPIO uptake (n=8, 0.24 cm/y) despite having similar aneurysm diameters (5.4±0.6, 5.1±0.5, and 5.0±0.5 cm, respectively; P>0.05). In 1 patient with an inflammatory aneurysm, there was a strong and widespread uptake of USPIO extending beyond the aortic wall. Conclusions— Uptake of USPIO in abdominal aortic aneurysms identifies cellular inflammation and appears to distinguish those patients with more rapidly progressive abdominal aortic aneurysm expansion. This technique holds major promise as a new method of risk-stratifying patients with abdominal aortic aneurysms that extends beyond the simple anatomic measure of aneurysm diameter. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00794092.

Fractal analysis of retinal vessels suggests that a distinct vasculopathy causes lacunar stroke

Objectives: Lacunar strokes account for 25% of all ischemic strokes and may represent the cerebral manifestation of a systemic small vessel vasculopathy of unknown etiology. Altered retinal vessel fractal dimensions may act as a surrogate marker for diseased cerebral vessels. We used a cross-sectional study to investigate fractal properties of retinal vessels in lacunar stroke. Methods: We recruited patients presenting with lacunar stroke and patients with minor cortical stroke as controls. All patients were examined by a stroke expert and had MRI at presentation. Digital retinal photographs were taken of both eyes. Monofractal and multifractal analyses were performed with custom-written semiautomated software. Results: We recruited 183 patients. Seventeen were excluded owing to poor photographic quality, leaving 166 patients (86 with lacunar and 80 with cortical stroke). The mean age was 67.3 years (SD 11.5 years). The patients with lacunar stroke were younger but the prevalence of diabetes, hypertension, and white matter hyperintensities did not differ between the groups. The mean Dbox (monofractal dimension) was 1.42 (SD 0.02), the mean D0 (multifractal dimension) 1.67 (SD 0.03). With multivariate analysis, decreased Dbox and D0 (both representing decreased branching complexity) were associated with increasing age and lacunar stroke subtype after correcting for hypertension, diabetes, stroke severity, and white matter hyperintensity scores. Conclusions: Lacunar stroke subtype and increasing age are associated with decreased fractal dimensions, suggesting a loss of branching complexity. Further studies should concentrate on longitudinal associations with other manifestations of cerebral small vessel disease.

Ultrasmall superparamagnetic particles of iron oxide in patients with acute myocardial infarction: early clinical experience.

Background—Inflammation following acute myocardial infarction (MI) has detrimental effects on reperfusion, myocardial remodelling, and ventricular function. Magnetic resonance imaging using ultrasmall superparamagnetic particles of iron oxide can detect cellular inflammation in tissues, and we therefore explored their role in acute MI in humans. Methods and Results—Sixteen patients with acute ST-segment elevation MI were recruited to undergo 3 sequential magnetic resonance scans within 5 days of admission at baseline, 24 and 48 hours following no infusion (controls; n=6) or intravenous infusion of ultrasmall superparamagnetic particles of iron oxide (n=10; 4 mg/kg). T2*-weighted multigradient-echo sequences were acquired and R2* values were calculated for specific regions of interest. In the control group, R2* values remained constant in all tissues across all scans with excellent repeatability (bias of −0.208 s−1, coefficient of repeatability of 26.96 s−1; intraclass coefficient 0.989). Consistent with uptake by the reticuloendothelial system, R2* value increased in the liver (84±49.5 to 319±70.0 s−1; P<0.001) but was unchanged in skeletal muscle (54±8.4 to 67.0±9.5 s−1; P>0.05) 24 hours after administration of ultrasmall superparamagnetic particles of iron oxide. In the myocardial infarct, R2* value increased from 41.0±12.0 s−1 (baseline) to 155±45.0 s−1 (P<0.001) and 124±35.0 s−1 (P<0.05) at 24 and 48 hours, respectively. A similar but lower magnitude response was seen in the remote myocardium, where it increased from 39±3.2 s−1 (baseline) to 80±14.9 s−1 (P<0.001) and 67.0±15.7 s−1 (P<0.05) at 24 and 48 hours, respectively. Conclusions—Following acute MI, uptake of ultrasmall superparamagnetic particles of iron oxide occurs with the infarcted and remote myocardium. This technique holds major promise as a potential method for assessing cellular myocardial inflammation and left ventricular remodelling, which may have a range of applications in patients with MI and other inflammatory cardiac conditions. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01323296.

Cognitive Correlates of Cerebral White Matter Lesions and Water Diffusion Tensor Parameters in Community-Dwelling Older People

Background: The biological basis of cognitive ageing is unknown. One underlying process might be disruption of white matter tracts connecting cortical regions. White matter lesions (WML) seen on structural MRI may disrupt cortical connections, but diffusion tensor MRI (DT-MRI) parameters – mean diffusivity () and fractional anisotropy (FA) – may reflect more subtle changes in white matter integrity. Here the relationships between WML load, DT-MRI parameters and cognition in a large cohort of elderly subjects with a very narrow age range were investigated. Methods: 105 community-dwelling volunteers underwent MRI and neuropsychological assessment. Seventy-two (68.6%) were female, and their mean age was 78.4 (SD 1.5) years. Scans were rated for WML load. and FA were measured from regions of interest in normal-appearing frontal and occipital white matter, and centrum semiovale. Results: and FA differed significantly among the three brain regions studied (p ≪ 0.01). increased with age (r = 0.22 to 0.35, p < 0.03), and was negatively correlated with FA (r = –0.20 to –0.51, p < 0.05) in all three regions. There was a trend towards increased WML load correlating with poorer cognitive function, and this was statistically significant for the Mini-Mental State Examination (ρ = –0.23, p = 0.02). was generally negatively correlated with cognitive test score, and FA was positively correlated. This pattern was more consistent for than for FA, and particularly for verbal fluency (: r = –0.22 to –0.27, p < 0.03), which measures executive function. Conclusions: DT-MRI parameters, in particular , are sensitive to early ultrastructural changes underlying cognitive ageing. Executive function may be the cognitive domain most sensitive to age-related decline in white matter tract integrity.

In Vivo Mononuclear Cell Tracking Using Superparamagnetic Particles of Iron Oxide Feasibility and Safety in Humans

Background— Cell therapy is an emerging and exciting novel treatment option for cardiovascular disease that relies on the delivery of functional cells to their target site. Monitoring and tracking cells to ensure tissue delivery and engraftment is a critical step in establishing clinical and therapeutic efficacy. The study aims were (1) to develop a Good Manufacturing Practice–compliant method of labeling competent peripheral blood mononuclear cells with superparamagnetic particles of iron oxide (SPIO), and (2) to evaluate its potential for magnetic resonance cell tracking in humans. Methods and Results— Peripheral blood mononuclear cells 1–5×109 were labeled with SPIO. SPIO-labeled cells had similar in vitro viability, migratory capacity, and pattern of cytokine release to unlabeled cells. After intramuscular administration, up to 108 SPIO-labeled cells were readily identifiable in vivo for at least 7 days using magnetic resonance imaging scanning. Using a phased-dosing study, we demonstrated that systemic delivery of up to 109 SPIO-labeled cells in humans is safe, and cells accumulating in the reticuloendothelial system were detectable on clinical magnetic resonance imaging. In a healthy volunteer model, a focus of cutaneous inflammation was induced in the thigh by intradermal injection of tuberculin. Intravenously delivered SPIO-labeled cells tracked to the inflamed skin and were detectable on magnetic resonance imaging. Prussian blue staining of skin biopsies confirmed iron-laden cells in the inflamed skin. Conclusions— Human peripheral blood mononuclear cells can be labeled with SPIO without affecting their viability or function. SPIO labeling for magnetic resonance cell tracking is a safe and feasible technique that has major potential for a range of cardiovascular applications including monitoring of cell therapies and tracking of inflammatory cells. Clinical Trial Registration— URL: http://www.clinicaltrials.gov; Unique identifier: NCT00972946, NCT01169935.

VAMPIRE: Vessel assessment and measurement platform for images of the REtina

We present VAMPIRE, a software application for efficient, semi-automatic quantification of retinal vessel properties with large collections of fundus camera images. VAMPIRE is also an international collaborative project of four image processing groups and five clinical centres. The system provides automatic detection of retinal landmarks (optic disc, vasculature), and quantifies key parameters used frequently in investigative studies: vessel width, vessel branching coefficients, and tortuosity. The ultimate vision is to make VAMPIRE available as a public tool, to support quantification and analysis of large collections of fundus camera images.

Observations From Non-Invasive Measures of Right Heart Hemodynamics in Left Ventricular Assist Device Patients

BACKGROUND Left ventricular assist devices (LVADs) reduce pulmonary vascular resistance (PVR) in patients with severe heart failure. The aim of this study was to noninvasively assess the effect of LVAD implantation on PVR and right-heart function. METHODS In 21 patients with HeartMate II LVADs, serial echocardiograms were reviewed prior to implantation and 1 and 6 months after implantation. Echocardiographic and Doppler indices of right-heart structure and function were measured along with LVAD settings, hemodynamics, and biochemistry, and the Minnesota Living With Heart Failure Questionnaire (MLHFQ) and 6-minute walk test were administered. RESULTS Comparing values before and 1 month after implantation, there were reductions in PVR (3.51 +/- 0.9 vs 2.0 +/- 0.5 Wood units, P < .0001), right ventricular (RV) systolic pressure (49 +/- 11 vs 34 +/- 7 mm Hg, P < .0001), and tricuspid regurgitation severity, with no change in RV size, RV fractional area change, or tricuspid annular plane systolic excursion. Patients with larger PVR reductions had better clinical status (MLHFQ score, 28 +/- 12 vs 60 +/- 29, P = .04; 6-minute walking distance, 1706 +/- 71 vs 1141 +/- 387 ft, P = .04). Patients with significant deteriorations in RV function had poorer clinical status (MLHFQ score, 79 +/- 13 vs 51 +/- 27, P = .04; 6-minute walking distance, 480 +/- 275 vs 1030 +/- 437 ft, P = .04). CONCLUSIONS Echocardiographically detected changes in right-heart hemodynamics were associated with symptomatic status after LVAD implantation.

Fractal analysis of the retinal vascular network in fundus images

Complexity of the retinal vascular network is quantified through the measurement of fractal dimension. A computerized approach enhances and segments the retinal vasculature in digital fundus images with an accuracy of 94% in comparison to the gold standard of manual tracing. Fractal analysis was performed on skeletonized versions of the network in 40 images from a study of stroke. Mean fractal dimension was found to be 1.398 (with standard deviation 0.024) from 20 images of the hypertensives sub-group and 1.408 (with standard deviation 0.025) from 18 images of the non-hypertensives subgroup. No evidence of a significant difference in the results was found for this sample size. However, statistical analysis showed that to detect a significant difference at the level seen in the data would require a larger sample size of 88 per group.

Validating retinal fundus image analysis algorithms: Issues and a proposal

This paper concerns the validation of automatic retinal image analysis (ARIA) algorithms. For reasons of space and consistency, we concentrate on the validation of algorithms processing color fundus camera images, currently the largest section of the ARIA literature. We sketch the context (imaging instruments and target tasks) of ARIA validation, summarizing the main image analysis and validation techniques. We then present a list of recommendations focusing on the creation of large repositories of test data created by international consortia, easily accessible via moderated Web sites, including multicenter annotations by multiple experts, specific to clinical tasks, and capable of running submitted software automatically on the data stored, with clear and widely agreed-on performance criteria, to provide a fair comparison.