Paul A. Armitage

Lacunar stroke is associated with diffuse blood–brain barrier dysfunction†

Lacunar stroke is common (25% of ischemic strokes) and mostly because of an intrinsic cerebral microvascular disease of unknown cause. Although considered primarily to be an ischemic process, the vessel and tissue damage could also be explained by dysfunctional endothelium or blood–brain barrier (BBB) leak, not just ischemia. We tested for subtle generalized BBB leakiness in patients with lacunar stroke and control patients with cortical ischemic stroke.

A theoretical study of the effect of experimental noise on the measurement of anisotropy in diffusion imaging

Diffusion tensor imaging (DTI) is a modality known to be highly sensitive to the detrimental effects of experimental noise. Here, using Monte Carlo simulations, we compare and contrast how noise complicates the measurement of diffusion anisotropy in diffusion tensor and conventional diffusion-weighted imaging (DWI). As the signal-to-noise ratio (SNR) decreases below a value of approximately 20, the eigenvalues (lambda(i)) of the diffusion tensor D are found to diverge rapidly from their true values, with the result that the measured anisotropy can be significantly in error and isotropic structures falsely assigned a high level of anisotropy. The effect of noise on the rotationally variant indices, calculated from a conventional diffusion-weighted imaging experiment, is found to be much less insidious, because the apparent diffusion coefficients (ADCs) diverge only slowly as the signal-to-noise decreases. Thus, although rotationally variant indices almost always underestimate the true diffusion anisotropy, they show only a small susceptibility to experimental noise and hence, are preferred to their rotationally invariant counterparts when the signal-to-noise ratio is small.

Comparison of 10 Different Magnetic Resonance Perfusion Imaging Processing Methods in Acute Ischemic Stroke Effect on Lesion Size, Proportion of Patients With Diffusion/Perfusion Mismatch, Clinical Scores, and Radiologic Outcomes

Background and Purpose— Several methods are available to assess the magnetic resonance perfusion lesion in acute ischemic stroke. We tested 10 of these to compare perfusion lesion sizes and to assess the relation to clinical scores and final infarct extent. Methods— We recruited patients with acute ischemic stroke, performed diffusion- and perfusion-weighted imaging, and recorded stroke severity at baseline, final infarct size on T2-weighted imaging at ≥1 month, and Rankin Scale score at 3 months. We calculated 10 perfusion parameters (6 of mean transit time, MTT; 3 of cerebral blood flow; 1 of cerebral blood volume; 7 relative and 3 quantitative), measured the perfusion-weighted imaging lesion and diffusion/perfusion mismatch volumes, and compared each with clinical and radiologic outcomes. Results— Among 32 patients, the median perfusion lesion volume varied from 0 to 14 882 voxels (P<0.0001); the proportion of patients with mismatch varied from 9% to 72% (P<0.05), depending on the perfusion parameter. Five measures of relative MTT were associated with baseline National Institutes of Health Stroke Scale score; 1 (arrival time fitted) was also associated with clinical outcome. Final infarct size was most strongly associated with MTT measures, including arrival time fitted. There was no advantage of quantitative perfusion measures and no relation between mismatch presence/absence and infarct expansion with any of the 10 perfusion measures. Conclusions— Perfusion lesion size differs markedly depending on the parameter calculated. Relative perfusion parameters performed as well as quantitative ones. Some parameters (mainly representing MTT measures) were correlated with clinical scores; others were correlated with final infarct size; and arrival time fitted was correlated with both. These findings should be validated in other datasets. A consensus is required on which perfusion measurement and processing methods should be used.

Do Acute Diffusion- and Perfusion-Weighted MRI Lesions Identify Final Infarct Volume in Ischemic Stroke?

Background and Purpose— An acute mismatch on diffusion-weighted MRI (DWI) and perfusion-weighted MRI (PWI) may represent the “tissue-at-risk.” It is unclear which “semiquantitative” perfusion parameter most closely identifies final infarct volume. Methods— Acute stroke patients underwent DWI and PWI (dynamic-susceptibility contrast imaging) on admission (baseline), and T2-weighted imaging (T2WI) at 1 or 3 months after stroke. “Semiquantitative” mean transit time (MTTsq=first moment of concentration/time curve), cerebral blood volume (CBVsq=area under concentration/time curve), and cerebral blood flow (CBFsq=CBVsq/MTTsq) were calculated. DWI and PWI lesions were measured at baseline and final infarct volume on T2WI acquired ≥1 month after stroke. Baseline DWI, CBFsq, and MTTsq lesion volumes were compared with final T2WI lesion volume. Results— Among 46 patients, baseline DWI and CBFsq lesions were not significantly different from final T2WI lesion volume, but baseline MTTsq lesions were significantly larger. The correlation with final T2WI lesion volume was strongest for DWI (Spearman rank correlation coefficient &rgr;=0.68), intermediate for CBFsq (&rgr;=0.55), and weakest for MTTsq (&rgr;=0.49) baseline lesion volumes. Neither DWI/CBFsq nor DWI/MTTsq mismatch predicted lesion growth; lesion growth was equally common in those with and without mismatch. Conclusions— Of the 2 PWI parameters, CBFsq lesions most closely identifies, and MTTsq overestimates, final T2WI lesion volume. “DWI/PWI mismatch” does not identify lesion growth. Patients without “DWI/PWI mismatch” are equally likely to have lesion growth as those with mismatch and should not be excluded from acute stroke treatment.

MR diffusion-weighted imaging and outcome prediction after ischemic stroke

Background: MR diffusion-weighted imaging (DWI) shows acute ischemic lesions early after stroke so it might improve outcome prediction and reduce sample sizes in stroke treatment trials. Previous studies of DWI and outcome produced conflicting results. Objective: To determine whether DWI lesion characteristics independently predict outcome in a broad range of patients with acute stroke. Methods: The authors recruited hospital-admitted patients with all severities of suspected stroke, assessed stroke severity on the NIH Stroke Scale (NIHSS), performed early brain DWI, and assessed outcome at 3 months (modified Rankin Scale). Clinical data and DWI lesion parameters were evaluated in a logistic regression model to identify independent predictors of outcome at 3 months and a previously described “Three-Item Scale” (including DWI) was tested for outcome prediction. Results: Among 82 patients (mean NIHSS 7.1 [±6.3 SD]), the only independent outcome predictors were age and stroke severity. Neither DWI lesion volume nor apparent diffusion coefficient nor the previously described Three-Item Scale predicted outcome independently. Comparison with previous studies suggested that DWI may predict outcome only in patients with more severe cortical ischemic strokes. Conclusions: Across a broad range of stroke severities, diffusion-weighted imaging (DWI) did not predict outcome beyond that of key clinical variables. Thus, DWI is unlikely to reduce sample sizes in acute stroke trials assessing functional outcome, especially where estimated treatment effects are modest.

Blood-brain barrier permeability in Alzheimer's disease: a case-control MRI study.

Blood-brain barrier (BBB) dysfunction may contribute to the risk of Alzheimers disease (AD). Dynamic contrast-enhanced magnetic resonance imaging (MRI) was performed repeatedly nine times before and up to 30 min following a 20 ml Gd-DTPA bolus injection in 15 AD participants and 15 healthy older people. For each participant, small circular regions of interest (size: 9 voxels) were placed to sample widely the deep gray matter (12 regions), cortical gray matter (72 regions), white matter (72 regions) and CSF (8 regions) as well as the basilar and internal carotid arteries (3 regions). Data were analysed using mixed effects models. There was no overall significant difference for AD subjects versus controls, but there was a significant effect for the time-by-AD interaction. Estimated marginal means remained essentially unchanged in AD subjects, but increased slowly after 15 min in healthy controls. An initial rise in gray matter MRI signal intensity followed by a later increase was also seen in AD participants after adjusting for CSF MRI signal intensities. The data suggest that BBB permeability is present even at an early stage of AD. Though the extent of leakage was no greater than that of non-demented people of a similar age in this small sample, the temporal pattern differed, indicating different blood-brain-CSF compartmental kinetics.

The relationship between stroke severity (NIHSS) and lactate in brain sub-regions in acute ischemic stroke.

Cerebrolysin (Cere) is a compound with neurotrophic activity shown to be effective in Alzheimers disease in earlier trials. The efficacy and safety of three dosages of Cere were investigated in this randomized, double‐blind, placebo‐controlled, study. Two hundred and seventy‐nine patients were enrolled (69 Cere 10 ml; 70 Cere 30 ml; 71 Cere 60 ml and 69 placebo). Patients received iv infusions of 10, 30, 60 ml Cere or placebo 5 days/week for the first 4 weeks and thereafter, two iv infusions per week for 8 weeks. Effects on cognition and clinical global impressions were evaluated 4, 12 and 24 weeks after the beginning of the infusions using the CIBIC+ and the modified Alzheimers Disease Assessment Scale (ADAS)‐cog. At week 24, significant improvement of cognitive performance on the ADAS‐cog (P = 0.038) and global function (CIBIC+; P > 0.001) was observed for the 10 ml dose. The 30 and 60 ml doses showed significant improvement of the global outcome but failed to show significant improvement of cognition. The results are consistent with a reversed U‐shaped dose–response relationship for Cere. The percentage of patients reporting adverse events was similar across all study groups. Cere treatment was well tolerated and led to significant, dose‐dependent improvement of cognition and global clinical impression.

Is diffusion imaging appearance an independent predictor of outcome after ischemic stroke

Background: MR diffusion-weighted imaging (DWI) in ischemic stroke can be quantified by calculating the apparent diffusion coefficient (ADC) or measuring lesion volume. Objective: To clarify the association between DWI lesion parameters, clinical stroke severity at baseline, and the relationship with functional outcome. Methods: Consecutive patients with stroke were categorized for stroke type (Oxford Community Stroke Project Classification [OCSP]) and severity (Canadian Neurologic Scale [CN Scale]) before DWI. The ratio of the trace of the apparent diffusion tensor in the ischemic lesion to the mirror image area in the contralateral hemisphere was calculated (r). The volume of the visible lesion on DWI was measured. Any visible lesion on T2-weighted imaging (T2WI) was noted. All assessments were blind to all other information. A blinded observer obtained a 6-month Rankin score. Univariate and multivariate analyses were performed to test for independent associations with outcome. Results: In 108 patients, those with lower (i.e., more abnormal) r values had more severe strokes according to the CN Scale (p = 0.01) and the OCSP stroke type (p = 0.002), a large lesion on DWI (p = 0.05), a visible lesion on T2WI (p = 0.001), and poor 6-month functional outcome (p = 0.009). However, on logistic regression, neither r nor DWI lesion volume were independent predictors of 6-month outcome over and above age and stroke severity. Conclusion: The r is associated with functional outcome, but that is because it and DWI lesion volume are also associated with stroke severity. Although DWI lesion features are univariate surrogate outcome predictors, the authors were unable to show that they were independent outcome predictors in the current study. Differences between these and other results may be due to differences in study design, sample size, and case mix.

Extracting and visualizing physiological parameters using dynamic contrast-enhanced magnetic resonance imaging of the breast

An analysis procedure is presented that enables the acquisition and visualization of physiologically relevant parameters using dynamic contrast-enhanced magnetic resonance imaging. The first stage of the process involves the use of a signal model that relates the measured magnetic resonance signal to the contrast agent concentration. Since the model requires knowledge of the longitudinal relaxation time T(1), a novel optimization scheme is presented which ensures a reliable measurement. Pharmacokinetic modelling of the observed contrast agent uptake is then performed to obtain physiological parameters relating to microvessel leakage permeability and volume fraction and the assumptions made in the derivation of these parameters are discussed. A simple colour representation is utilized that enables the relevant physiological information to be conveyed to the clinician in a visually efficient and meaningful manner. A second representation, based on vector maps, is also devised and it is demonstrated how this can be used for malignant tumour segmentation. Finally, the procedure is applied to 14 pre- and post-chemotherapy breast cases to demonstrate the clinical value of the technique. In particular, the apparent improved representation of tissue vascularity when compared to conventional methods and the implications for this in treatment assessment are discussed.

Blood–Brain Barrier Permeability and Long-Term Clinical and Imaging Outcomes in Cerebral Small Vessel Disease

Background and Purpose— Increased blood–brain barrier (BBB) permeability occurs in cerebral small vessel disease. It is not known if BBB changes predate progression of small vessel disease. Methods— We followed-up patients with nondisabling lacunar or cortical stroke and BBB permeability magnetic resonance imaging after their original stroke. Approximately 3 years later, we assessed functional outcome (Oxford Handicap Score, poor outcome defined as 3–6), recurrent neurological events, and white matter hyperintensity (WMH) progression on magnetic resonance imaging. Results— Among 70 patients with mean age of 68 (SD±11) years, median time to clinical follow-up was 39 months (interquartile range, 30–45) and median Oxford Handicap Score was 2 (interquartile range, 1–3); poor functional outcome was associated with higher baseline WMH score (P<0.001) and increased basal ganglia BBB permeability (P=0.046). Among 48 patients with follow-up magnetic resonance imaging, WMH progression at follow-up was associated with baseline WMH (ANCOVA P<0.0001) and age (ANCOVA P=0.032). Conclusions— Further long-term studies to evaluate the role of BBB dysfunction in progression of small vessel disease are required in studies that are large enough to account for key prognostic influences such as baseline WMH and age.