Majaz Moonis

Amyloid Deposition Begins in the Striatum of Presenilin-1 Mutation Carriers from Two Unrelated Pedigrees

The amyloid cascade hypothesis suggests that the aggregation and deposition of amyloid-β protein is an initiating event in Alzheimers disease (AD). Using amyloid imaging technology, such as the positron emission tomography (PET) agent Pittsburgh compound-B (PiB), it is possible to explore the natural history of preclinical amyloid deposition in people at high risk for AD. With this goal in mind, asymptomatic (n = 5) and symptomatic (n = 5) carriers of presenilin-1 (PS1) mutations (C410Y or A426P) that lead to early-onset AD and noncarrier controls from both kindreds (n = 2) were studied with PiB–PET imaging and compared with sporadic AD subjects (n = 12) and controls from the general population (n = 18). We found intense and focal PiB retention in the striatum of all 10 PS1 mutation carriers studied (ages 35–49 years). In most PS1 mutation carriers, there also were increases in PiB retention compared with controls in cortical brain areas, but these increases were not as great as those observed in sporadic AD subjects. The two PS1 mutation carriers with a clinical diagnosis of early-onset AD did not show the typical regional pattern of PiB retention observed in sporadic AD. Postmortem evaluation of tissue from two parents of PS1C410Y subjects in this study confirmed extensive striatal amyloid deposition, along with typical cortical deposition. The early, focal striatal amyloid deposition observed in these PS1 mutation carriers is often is not associated with clinical symptoms.

HMG-CoA Reductase Inhibitors Improve Acute Ischemic Stroke Outcome

Background and Purpose— Statins reduce the risk of stroke recurrence, but the benefits of statins in improving outcome of acute stroke patients have not been well explored. Methods— We assessed potential effects of statins initiated before or within 4 weeks of stroke on 90-day outcome. Favorable outcomes were National Institutes of Health Stroke Scale (NIHSS) score ≤2 at 12 weeks and modified Rankin Scale (mRS) ≤2. Results— Before stroke, 129 patients were receiving statins, 123 initiated statins within 4 weeks, and 600 patients were not on statins. Multivariate logistic regression analysis demonstrated that poststroke statins were associated with a significant probability of a favorable outcome at 12 weeks [NIHSS (P=0.002; OR, 1.92; CI, 1.27 to 2.91) and mRS (P=0.033; OR, 1.57; CI, 1.04 to 2.38)], whereas prestroke statins demonstrated a trend toward significance. Conclusions— These preliminary results suggest that statin use may improve outcome of acute ischemic stroke.

Familial Alzheimer disease: Decreases in CSF Aβ42 levels precede cognitive decline

CSF amyloid β-peptide 42 (Aβ42) levels in presymptomatic subjects with pathogenic mutations in the PS1 gene are significantly lower than in an age-matched control group. Consequently, in these subjects, there is a window of opportunity estimated as at least 4 to 12 years to evaluate the ability of any putative prophylactic therapy to decrease, arrest, or reverse abnormalities in Aβ42 metabolism many years before clinical symptoms of Alzheimer disease are otherwise likely to occur.

Leukoaraiosis Predicts Poor 90-Day Outcome after Acute Large Cerebral Artery Occlusion

Background: To date limited information regarding outcome-modifying factors in patients with acute intracranial large artery occlusion (ILAO) in the anterior circulation is available. Leukoaraiosis (LA) is a common finding among patients with ischemic stroke and has been associated with poor post-stroke outcomes but its association with ILAO remains poorly characterized. This study sought to clarify the contribution of baseline LA and other common risk factors to 90-day outcome (modified Rankin Scale, mRS) after stroke due to acute anterior circulation ILAO. Methods: We retrospectively analyzed 1,153 consecutive patients with imaging-confirmed ischemic stroke during a 4-year period (2007–2010) at a single academic institution. The final study cohort included 87 patients with acute ILAO subjected to multimodal CT imaging within 24 h of symptom onset. LA severity was assessed using the van Swieten scale on non-contrast CT. Leptomeningeal collaterals were graded using CT angiogram source images. Hemorrhagic transformation (HT) was determined on follow-up CT. Multivariate logistic regression controlling for HT, treatment modality, demographic, as well as baseline clinical and imaging characteristics was used to identify independent predictors of a poor outcome (90-day mRS >2). Results: The median National Institutes of Health Stroke Scale (NIHSS) at baseline was 15 (interquartile range 9–21). Twenty-four percent of the studied patients had severe LA. They were more likely to have hypertension (p = 0.028), coronary artery disease (p = 0.015), poor collaterals (p < 0.001), higher baseline NIHSS (p = 0.003), higher mRS at 90 days (p < 0.001), and were older (p = 0.002). Patients with severe LA had a uniformly poor outcome (p < 0.001) irrespective of treatment modality. Poor outcome was independently associated with higher baseline NIHSS (p < 0.001), worse LA (graded and dichotomized, p < 0.001), reduced leptomeningeal collaterals (graded and dichotomized, p < 0.001), presence of HT (p < 0.001), presence of parenchymal hemorrhages (p = 0.01), baseline mRS (p = 0.002), and older age (p = 0.043). The association between severe LA (p = 0.0056; OR 13.86; 95% CI 1.94–∞) and baseline NIHSS (p = 0.0001; OR 5.11; 95% CI 2.07–14.49 for each 10-point increase) with poor outcome maintained after adjustment for confounders in the final regression model. In this model, there was no significant association between presence of HT and poor outcome (p = 0.0572). Conclusion: Coexisting LA may predict poor functional outcome in patients with acute anterior circulation ILAO independent of other known important outcome predictors such as comorbid state, admission functional deficit, collateral status, hemorrhagic conversion, and treatment modality.

Considering the Role of Heparin and Low-Molecular-Weight Heparins in Acute Ischemic Stroke

Background and Purpose— The utility of parenteral anticoagulation therapy in acute ischemic stroke has engendered much controversy and discussion. Recent studies of low-molecular-weight heparins in multiple acute stroke subtypes have not demonstrated improved outcome or reduced recurrence risk. Beneficial treatment effects may occur in subgroups such as patients with large artery atherothrombotic stroke, but further studies will be needed to prove this possibility. Summary of Review— The benefits of unfractionated intravenous heparin for reducing early stroke recurrence and improving outcome remain to be established, with the current lack of appropriately powered trials in stroke subgroups at high risk for such early recurrence. To most clinicians, the primary reason to use early intravenous anticoagulation is to prevent early stroke recurrence, not to improve outcome of an established stroke. Unfortunately, effects of reduction of recurrent stroke risk may be counterbalanced by a substantial increased risk of intracerebral hemorrhage with intravenous anticoagulation. Conclusions— Unfractionated intravenous heparin should therefore not be used routinely in acute ischemic stroke, but it may be considered in select stroke groups at high risk for early recurrent ischemic events (ie, patients with atrial fibrillation or acute myocardial infarction and large mural thrombi). However, even in these select populations, new clinical trials will be needed to define the risk-benefit ratio.

Leukoaraiosis and Sex Predict the Hyperacute Ischemic Core Volume

Background and Purpose— Leukoaraiosis (LA) and male sex have been associated with decreased cerebrovascular reactivity, which potentially adversely affects tissue viability in acute stroke. Therefore, we aimed to elucidate the contribution of LA-severity and sex to the extent of the hyperacute ischemic core volume after intracranial large artery occlusion. Methods— We analyzed data from 87 patients with acute intracranial large artery occlusion who had acute multimodal computed tomography-imaging. LA-severity was assessed using the van Swieten scale on noncontrast computed tomography. Computed tomography perfusion data were analyzed using automatic calculation of the mean transit time and hyperacute cerebral blood volume defects. Multivariate linear and logistic regression analyses were used to identify independent predictors of the hyperacute infarct-volume. Results— Severe LA (van Swieten Scale, 3–4; odds ratio, 43.22; 95% CI, 6.26–298.42; P<0.001) and male sex (odds ratio, 7.52; 95% CI, 1.38–40.86; P=0.020) were independently associated with a hyperacute cerebral blood volume-lesion >25 mL on multivariate logistic regression analysis. Multivariate linear regression analysis confirmed the association between severe LA (P<0.001) and male sex (P=0.01) with larger cerebral blood volume-lesions. There was no significant difference in the absolute or relative mean transit time-lesion volumes when stratified by LA-severity or sex. Women had significantly smaller cerebral blood volume-lesion volumes compared with men (P=0.036). Conclusions— Severe LA and male sex are associated with larger infarct cores, which adds to the notion that sex and LA alter the brain’s intrinsic susceptibility to acute cerebral ischemia. Future, larger studies are needed to confirm our observation that women have smaller core volumes and its significance.

Transcranial Laser Therapy in Acute Stroke Treatment Results of Neurothera Effectiveness and Safety Trial 3, a Phase III Clinical End Point Device Trial

Background and Purpose— On the basis of phase II trials, we considered that transcranial laser therapy could have neuroprotective effects in patients with acute ischemic stroke. Methods— We studied transcranial laser therapy in a double-blind, sham-controlled randomized clinical trial intended to enroll 1000 patients with acute ischemic stroke treated ⩽24 hours after stroke onset and who did not undergo thrombolytic therapy. The primary efficacy measure was the 90-day functional outcome as assessed by the modified Rankin Scale, with hierarchical Bayesian analysis incorporating relevant previous data. Interim analyses were planned after 300 and 600 patients included. Results— The study was terminated on recommendation by the Data Monitoring Committee after a futility analysis of 566 completed patients found no difference in the primary end point (transcranial laser therapy 140/282 [49.6%] versus sham 140/284 [49.3%] for good functional outcome; modified Rankin Scale, 0–2). The results remained stable after inclusion of all 630 randomized patients (adjusted odds ratio, 1.024; 95% confidence interval, 0.705–1.488). Conclusions— Once the results of the interim futility analysis became available, all study support was immediately withdrawn by the capital firms behind PhotoThera, and the company was dissolved. Proper termination of the trial was difficult but was finally achieved through special efforts by former employees of PhotoThera, the CRO Parexel and members of the steering and the safety committees. We conclude that transcranial laser therapy does not have a measurable neuroprotective effect in patients with acute ischemic stroke when applied within 24 hours after stroke onset. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01120301.

Use of telemedicine to increase thrombolysis and advance care in acute ischemic stroke.

The use of the only proven therapy for acute ischemic stroke, intravenous tissue plasminogen activator (tPA), remains disappointingly low. One potential way to increase the use of tPA is by the implementation of telemedicine stroke care networks. Preliminary data from several studies indicate that the safe and expanded use of tPA for ischemic stroke can be accomplished with the help of telemedicine. Telemedicine stroke care networks can also be used in the future to enhance stroke diagnosis with advanced CT and MRI technology and to potentially increase the number of patients referred to tertiary stroke centers for intra-arterial therapies. It is highly likely that telemedicine stroke care will substantially enhance acute stroke therapy for remote and underserved populations.

Leukoaraiosis Predicts Cortical Infarct Volume After Distal Middle Cerebral Artery Occlusion

Background and Purpose— Leukoaraiosis (LA) predominantly affects the subcortical white matter, but mounting evidence suggests an association with cortical microvascular dysfunction and potentially decreased cortical ischemic tolerance. Thus, we sought to assess whether preexisting LA is predictive of the cortical infarct volume after middle cerebral artery branch occlusion and whether it relates to a worse outcome. Methods— We analyzed data from 117 consecutive patients with middle cerebral artery branch occlusion as documented by admission computed tomography angiography. Baseline clinical, laboratory, and outcome data, as well as final cortical infarct volumes, were retrospectively analyzed from a prospectively collected database. LA severity was assessed on admission computed tomography using the van Swieten scale grading the supratentorial white matter hypoattenuation. Infarct volume predicting a favorable 90-day outcome (modified Rankin Scale score ⩽2) was determined by receiver operating characteristic curves. Multivariable linear and logistic regression analyses were used to identify independent predictors of the final infarct volume and outcome. Results— Receiver operating characteristic curve analyses indicated that a final infarct volume of ⩽27 mL best predicted a favorable 90-day outcome. Severe LA (odds ratio, 11.231; 95% confidence interval, 2.526–49.926; P=0.001) was independently associated with infarct volume >27 mL. Severe LA (odds ratio, 3.074; 95% confidence interval, 1.055–8.961; P=0.040) and infarct volume >27 mL (odds ratio, 9.156; 95% confidence interval, 3.191–26.270; P<0.001) were independent predictors of a poor 90-day outcome (modified Rankin Scale, 3–6). Conclusions— The presence of severe, subcortical LA contributes to larger cortical infarct volumes and worse functional outcomes adding to the notion that the brain is negatively affected beyond LA’s macroscopic boundaries.

Imaging of Acute Stroke

The utility of diagnostic imaging during the critical first few hours after stroke onset has many important applications. First and foremost, imaging technologies that can reliably detect and quantify the location of acute stroke will greatly enhance the clinician’s ability to accurately diagnose individual stroke patients. Secondly, if imaging technology could provide information about the likely severity of the ischemic injury, patient prognosis and management would be enhanced. The possibility of potentially distinguishing severely injured and likely irreversible ischemic brain tissue from ischemic tissue likely not yet irreversibly injured may soon be attainable. The ability of imaging technology to reliably distinguish the status of focally ischemic brain will presumably dramatically impact upon patient management. This information, along with the data about the severity and extent of blood flow and tissue perfusion abnormalities, will help acute stroke care evolve beyond rigid time windows to individualized, pathophysiologically based treatment decisions. Not only will decisions to treat or not be made based upon imaging-derived status, but also the most appropriate type of therapy to be employed, i.e. thrombolysis, neuroprotection, therapy to reduce secondary reperfusion-related injury or combinations of these modalities. In this brief and necessarily incomplete overview of acute stroke imaging, the focus will be on new developments in CT and MRI.