John Ly

Ischemic Thresholds for Gray and White Matter. A Diffusion and Perfusion Magnetic Resonance Study

Background and Purpose— Although gray matter (GM) and white matter (WM) have differing neurochemical responses to ischemia in animal models, it is unclear whether this translates into differing thresholds for infarction. We studied this issue in ischemic stroke patients using magnetic resonance (MR) techniques. Methods— MR studies were performed in patients with acute hemispheric ischemic stroke occurring within 24 hours and at 3 months. Cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), and apparent diffusion coefficient (ADC) were calculated. After segmentation based on a probabilistic map of GM and WM, tissue-specific diffusion and perfusion thresholds for infarction were established. Results— Twenty-one patients were studied. Infarction thresholds for CBF were significantly higher in GM (median 34.6 mL/100 g per minute, interquartile range 26.0 to 38.8) than in WM (20.8 mL/100 g per minute; interquartile range 18.0 to 25.9; P<0.0001). Thresholds were also significantly higher in GM than WM for CBV (GM: 1.67 mL/100 g; interquartile range 1.39 to 2.17; WM: 1.19 mL/100 g; interquartile range 0.94 to 1.53; P<0.0001), ADC (GM: 918×10−6 mm2/s; 868 to 975×10−6; WM: 805×10−6; 747 to 870×10−6; P<0.001), and there was a trend toward a shorter MTT in GM (GM 4.94 s, 4.44 to 5.38; WM 5.15, 4.11 to 5.68; P=0.11). Conclusions— GM has a higher infarction threshold for CBF, CBV, and ADC than WM in patients within 24 hours of ischemic stroke onset. Hence, when assessing patients for potential therapies, tissue-specific rather than whole-brain thresholds may be a more precise measure of predicting the likelihood of infarction.

Silent Infarcts and Cerebral Microbleeds Modify the Associations of White Matter Lesions With Gait and Postural Stability Population-Based Study

Background and Purpose— Although cerebral white matter lesions (WMLs), silent infarcts (SIs), and microbleeds (MBs) are individually associated with poorer gait and balance, it is unknown if they interact. We studied the interactions of WML volume with SI and MB on gait and postural stability. Methods— Participants in a population-based study aged 60 to 86 years underwent brain MRI, computerized gait measurement, and a physiological profile assessment of postural stability. Segmentation procedures and standard rating methods were used to measure WML, SI, and MB. Linear regression was used to test interactions between lesions on gait and postural stability, adjusting for age, sex, and total intracranial volume. Results— There were 395 participants (mean age, 72 years; SD, 7.0). SIs were predominantly located in subcortical frontal white matter and in deep gray structures, and MBs were largely lobar. Participants with SI or MB had higher WML volumes than those without (P<0.001 and P=0.05, respectively). The presence of SI (P for interaction=0.01) or MB (P for interaction <0.01) magnified the adverse association of WML volume with gait. SI (P for interaction=0.02), but not MB, magnified the adverse association of WML volume with postural stability. Conclusions— Subclinical cerebrovascular lesions are adversely associated with gait and postural stability in older people in a cumulative fashion.

Neuroprotection and thrombolysis: combination therapy in acute ischaemic stroke

The administration of oral aspirin within 48 h and tissue plasminogen activator within 3 h of ischaemic stroke onset remain the only treatments that have been shown to have clinical benefit. There has been much excitement about neuroprotection over the last two decades, as it may minimise the harmful effects of ischaemic neuronal damage. Although each step along the ischaemic cascade offers a potential target for therapeutic intervention, and neuroprotection has shown benefit in animal studies, this has been difficult to translate to humans. Some hope has been offered by the recent finding that the free radical scavenger NXY-059 may improve outcomes in patients presenting within 6 h of onset of ischaemic stroke. There is logic to the idea that neuroprotection may be most effective when reperfusion has occurred with thrombolysis, as the neuroprotectant will have greater access to ischaemic tissue and the opportunity is presented to minimise free radical-mediated reperfusion injury. Numerous studies in animal models support this view, but the concept has not, as yet, been rigorously tested in humans.

Cerebral β-amyloid detected by Pittsburgh compound B positron emission topography predisposes to recombinant tissue plasminogen activator-related hemorrhage†‡

Cerebral amyloid angiopathy (CAA) may be an important predisposing factor for the hemorrhagic complications of recombinant tissue‐type plasminogen activator (rt‐PA) therapy. We studied patients treated within 3 hours of onset of ischemic stroke with rt‐PA using positron emission tomography to compare Pittsburgh compound B (PiB) (a cerebral β‐amyloid ligand) retention in those with and without parenchymal hemorrhage (PH) and normal controls. Neocortical PiB retention was higher among patients with PH compared with patients without PH and normal controls, suggesting underlying CAA as a predisposing factor for rt‐PA–related hemorrhage. This finding may provide an impetus for the development of a more practical rapid pretreatment screening technique. Ann Neurol 2010

Penumbral mismatch is underestimated using standard volumetric methods and this is exacerbated with time.

Background and aim: The mismatch between perfusion weighted images (PWI) and diffusion weighted images (DWI) using MR is increasingly being applied in patient selection for therapeutic trials. Two approaches to the calculation of the mismatch volume exist—the commonly used volumetric and the more precise co-registration method, the latter of which considers lesion topography. That there are differences in the mismatch volume analysed by each method and that these are time dependent was hypothesised. Methods: Patients within 48 h of ischaemic stroke onset had baseline MR PWI/DWI mismatch and T2 outcome volumes at 3 months. Volumetric mismatch volume was defined as PWI minus DWI lesion. Co-registration mismatch volume was defined as the PWI defect lesion not overlapped by the co-registered DWI lesion. Results: 72 patients of median age 74.0 years were studied. Median baseline MR was at 5.9 h (IQR 3.0, 20.4 h) after stroke onset. Consistent underestimation of the mismatch volume occurred using the volumetric method (volumetric median 9.3 ml, IQR 0, 63 ml; co-registration median 20.1 ml, IQR 3.2, 69.8 ml; p<0.0001). This difference increased with time from stroke onset (p = 0.006). Conclusions: Volumetric analysis consistently underestimates the PWI/DWI mismatch volume compared with the more precise co-registration method. This effect increases with time.

Salvage of the PWI/DWI mismatch up to 48 h from stroke onset leads to favorable clinical outcome

Background and Purpose In acute ischemic stroke perfusion/diffusion-weighted image, mismatch using magnetic resonance imaging approximates the ischemic penumbra. For early time windows, mismatch salvage improves clinical outcomes, but uncertainty exists at later time epochs. We hypothesized that (a) mismatch may exist up to 48 h; (b) the proportion of mismatch salvage is time independent; and (c) when salvaged, it improves clinical outcomes. Methods Magnetic resonance imaging was performed within 48 h of ischemic stroke. Perfusion-weighted image was defined by relative Tmax two-second delay. Perfusion/diffusion-weighted image mismatch was the perfusion-weighted image not overlapped by the diffusion-weighted image when coregistered. Infarct volume and disability (modified Rankin Score) were assessed at three-months. Mismatch salvage was the region not overlapped by final infarction. Favorable outcome was defined as modified Rankin Score 0–1. Results Sixty-six patients were studied [mean age 69·9 years (standard deviation 13·1), initial median National Institute of Health Stroke Scale 9·0 (interquartile range 6·0, 18·3)]. There was no relationship between time of stroke onset and the proportion of mismatch salvaged (P = 0·73). Age (adjusted odds ratio = 0·92, 95% confidence interval 0·86–0·98, P = 0·01), initial National Institute of Health Stroke Scale (adjusted odds ratio = 0·80, 95% confidence interval 0·70–0·92, P < 0·01), mismatch volume (adjusted odds ratio = 0·98, 95% confidence interval 0·968–0·1, P = 0·05), and percentage of mismatch salvage (adjusted odds ratio = 1·04, 95% confidence interval 0·99–1·07, P = 0·05) were independently associated with favorable outcome. Conclusion Using coregistered perfusion/diffusion-weighted image criteria, mismatch persists up to 48 h post stroke. For the whole group, the proportion of mismatch salvage remains independent of time and, although the effect is small, its salvage is independently associated with improved clinical outcomes at three-months. Larger sample sizes are needed to determine the time limit for mismatch salvage.

Subacute Ischemic Stroke Is Associated With Focal 11C PiB Positron Emission Tomography Retention But Not With Global Neocortical Aβ Deposition

Background and Purpose— Conflicting evidence exists as to whether focal cerebral ischemia contributes to cerebral amyloid deposition. We aimed to look at A&bgr; deposits, detected by N-methyl-2-(4′-methylaminophenyl)-6-hydroxybenzothiazole (PiB) positron emission tomography, in patients with recent ischemic stroke. Specifically, we hypothesized that patients with recent ischemic stroke have higher local and neocortical PiB positron emission tomography retention and that this may be associated with major vascular risk factors. Methods— Ischemic stroke patients were studied using PiB positron emission tomography within 30 days and compared to age-matched controls. Distribution volume ratio maps were created using Logan graphical analysis with the cerebellar cortex as a reference. Results— Among the 21 ischemic stroke patients (median age, 76 years; interquartile range, 68–77), the ipsilateral peri-infarct region PiB retention was higher compared to the contralateral mirror region, with a PiB distribution volume ratio difference of 0.29 (95% CI, 0.2–0.44; P=0.001) at median 10 (interquartile range, 7–14) days after stroke. Two patients also had higher PiB retention within the infarct compared to the contralateral side. There was no difference in the neocortical PiB retention elsewhere in the brain among ischemic stroke patients compared with 22 age-matched normal controls (P=0.22). Among the risk factors in the ischemic stroke patients, diabetes was associated with a higher neocortical PiB retention (Spearman Rho=0.48; 95% CI, 0.28–0.72). Conclusions— PiB retention was higher in the peri-infarct region among patients with recent ischemic stroke. This did not translate into a higher global neocortical PiB retention except possibly in patients with diabetes. The cause of the focal PiB retention is uncertain and requires further investigation.

Fragmentation of the Classical Magnetic Resonance Mismatch “Penumbral” Pattern With Time

Background and Purpose— The classical mismatch pattern in the middle cerebral artery territory stroke on MR is defined by a central diffusion-weighted image core with surrounding mismatch tissue. Because of variable rates of tissue salvage, we hypothesized that this pattern may fragment over time and may be influenced by vessel patency, mismatch volume, and infarct core location. Methods— Patients were recruited with MR studies performed within 48 hours of ischemic stroke. Mismatch patterns based on diffusion-weighted/perfusion-weighted images were categorized as classical (majority of the diffusion-weighted image within the perfusion-weighted image lesion) or nonclassical (fragmented) patterns. The proportion of patterns was assessed with reference to time, vessel patency, mismatch volume, and infarct core location. Results— Sixty-seven patients (33 classical [49.3%] and 34 nonclassical patterns [50.7%]) were studied within 48 hours (median age, 74.0 years). Compared to the nonclassical pattern, the classical pattern had a shorter time to MR (3.4 hours vs 10.4 hours; P=0.004) and a larger mismatch volume (62.0 mL vs 3.5 mL; P<0.0001). The positive predictors for the classical pattern were earlier time, vessel occlusion, superficial core location, and larger mismatch volume. Conclusion— The classical mismatch pattern may fragment with time. Over 48 hours the classical pattern is seen earlier after stroke onset, with higher rates of vessel occlusion and larger mismatch volumes.

Convexity Subarachnoid Hemorrhage with PiB Positive Pet Scans: Clinical Features and Prognosis

Cerebral amyloid angiopathy (CAA) has been reported to present as convexity subarachnoid hemorrhage (cSAH). Lesser known is that cSAH can herald intracerebral hemorrhage (ICH) and ischemic lesions. We present seven new cases with 11C‐Pittsburgh compound B (PiB) positive positron emission tomography (PET) scans including two with biopsy, review the literature and comment on clinical and radiological findings.BACKGROUND Cerebral amyloid angiopathy (CAA) has been reported to present as convexity subarachnoid hemorrhage (cSAH). Lesser known is that cSAH can herald intracerebral hemorrhage (ICH) and ischemic lesions. We present seven new cases with 11C-Pittsburgh compound B (PiB) positive positron emission tomography (PET) scans including two with biopsy, review the literature and comment on clinical and radiological findings. METHODS Patients with cSAH identified on CT, underwent MR imaging and MR angiography to exclude intracranial aneurysm. Nonaneurysmal cSAH were further prospectively evaluated for amyloid angiopathy using PiB. Clinical and radiological features of cSAH, subsequent ICH and ischemic lesions were characterized. RESULTS Seven patients with nonaneurysmal cSAH fulfilled the Boston criteria for probable CAA. All had PiB PET scans consistent with CAA. Of the 4 patients who had contrast MR Imaging all had enhancement overlying the cSAH, followed by ICH in three cases. All patients presented with transient sensory symptoms. All patients had small punctate subcortical and cortical infarcts on diffusion-weighted MR imaging. Literature review revealed subsequent ICH in approximately 11/79 patients. CONCLUSION The finding of cSAH and PiB binding in our patients suggest underlying CAA. cSAH may be associated with ischemic lesion as well as future ICH occurrence.

Positron Emission Tomographic Imaging in Stroke Cross-Sectional and Follow-Up Assessment of Amyloid in Ischemic Stroke

Background and Purpose— Cardiovascular risk factors significantly increase the risk of developing Alzheimer disease. A possible mechanism may be via ischemic infarction–driving amyloid deposition. We conducted a study to determine the presence of &bgr;-amyloid in infarct, peri-infarct, and hemispheric areas after stroke. We hypothesized that an infarct would trigger &bgr;-amyloid deposition, with deposition over time. Methods— Patients were recruited within 40 days of acute ischemic stroke and imaged with computed tomographic or magnetic resonance imaging and Pittsburgh compound B (11C-PiB) positron emission tomographic scans. Follow-up positron emission tomographic scanning was performed in a subgroup ⩽18 months after the stroke event. Standardized uptake value ratios for regions of interest were analyzed after coregistration. Results— Forty-seven patients were imaged with 11C-PiB positron emission tomography. There was an increase in 11C-PiB accumulation in the stroke area compared with a reference region in the contralesional hemisphere, which was not statistically significant (median difference in standardized uptake value ratio, 0.07 [95% confidence interval, −0.06 to 0.123]; P=0.452). There was no significant increase in the accumulation of 11C-PiB in the peri-infarct region or in the ipsilesional hemisphere (median difference in standardized uptake value ratio, 0.04 [95% confidence interval, −0.02 to 0.10]; P=0.095). We repeated 11C-PiB positron emission tomography in 21 patients and found a significant reduction in accumulation of 11C-PiB between regions of interest (median difference in standardized uptake value ratio, −0.08 [95% confidence interval, −0.23 to −0.03]; P=0.04). Conclusions— There was no significant increase in 11C-PiB accumulation in or around the infarct. There was no increase in ipsilesional hemispheric 11C-PiB accumulation over time. We found no evidence that infarction leads to sustained or increased &bgr;-amyloid deposition ⩽18 months after stroke.