Diffusion tensor imaging in acute ischemic stroke: the role of anisotropy in determining the time of onset and predicting long-term motor outcome

Introducción: El infarto cerebral és una de las primeras causas de morbi-mortalidad en nuestra sociedad. La fibrinolisis intravenosa con activador tisular del plasminógeno es el tratamiento de elección en las primeras 4.5 horas del inicio de los síntomas. Aproximadamente en un tercio de los pacientes se desconoce el tiempo de evolución, por lo que la fibrinolisis estaría contraindicada. Existe un gran interés en detectar parámetros fiables para discriminar el tiempo de evolución de un infarto cerebral. El tensor de difusión (DTI, del inglés diffusion tensor imaging) por resonancia magnética (RM) es un nuevo método no invasive que permite estudiar la difusividad de las moléculas de agua en los tejidos. La DTI aporta información sobre el grado y direccionalidad de la difusividad del agua, expresada por la anisotropía fraccional (FA, fraccional anisotropy). Actualmente, no existe suficiente evidencia científica que sostenga que los índice anisotrópicos son importantes para determinar el tiempo de evolución de un infarto cerebral. Por otro lado, recientemente se ha demostrado que la afectación del tracto corticoespinal (TCE), una de las vías motoras principales que regula el movimiento voluntario de brazos y piernas, se asocia a mala evolución motora. Una predicción precoz y precisa del déficit motor contribuiría a un mejor manejo de los pacientes. Los índices anisotrópicos podrían ser biomarcadores subrogados de deficit motor a largo plazo. Objectivos: Los objetivos primarios de esta tesis son: (1) valorar los índices anisotrópicos en el parénquima cerebral afectado por el infarto y determinar el potencial predictivo para discriminar el tiempo de evolución de un infarto cerebral; (2) evaluar si la anisotropía del TCE se correlaciona con el deficit motor a largo plazo tras un infarto cerebral. Material y Métodos: Se evaluaron 60 pacientes consecutivos con infarto en territorio de la arteria cerebral media de menos de 12 horas de evolución. El déficit motor se valoraró mediante los subíndices motores (5a, 5b, 6a, 6b) de la escala National Institutes of Health Stroke Scale (m-NIHSS) al ingreso, día 3, 30, 90 y los dos años tras el ictus. La severidad del déficit motor se categorizó en tres grados: grado I (m-NIHSS total de 0), grado II (1-4) y grado III (5-8). El déficit motor a los 2 años de la evolución se valoró mediante la escala de Índice de Motricidad. Todos los estudios de RM se realizaron en un equipo de 1.5 T. La secuencia de DTI se adquirió en 15 direcciones. Resultados: La rFA en el TCE (p=0.001), ratio de diffusivitat media cortical (p=0.036) , coeficiente aparente de difusión cortical (p=0.009 ), ratio de señal T2 en el TCE (p=0.006) e hiperintensidad en FLAIR (p4.5 hours were rFA deep white matter (WM) (p=0.001), mean diffusivity ratio (rMD) cortical grey matter (GM) (p=0.036), apparent diffusion coefficient ratio (rADC) cortical GM (p=0.009), rT2 deep WM (p=0.006), and FLAIR (p4.5. The sensitivity, specificity, and positive and negative predictive values for infarct ≤4.5 h of onset by rFA deep WM > 0.970 were 93.8%, 84.6%, 88.2%, and 91.7%, respectively. On the other hand, lower rFA values correlated with motor deficit at day 30 (p<0.001; r=-0.801). Independent predictors of long-term motor outcome were rFA at day 30, infarct volume at day 3, motor deficit at day 3, motor deficit at day 30, and PLIC damage on admission. rFA at day 30 was the best predictor of long-term motor outcome (OR 35.45; 95%CI, 32.23-39.87; p<0.001). The best rFA cutoffs for discriminating good vs. intermediate and intermediate vs. poor outcome at 2 years were 0.978 and 0.685, respectively (AUC=0.99, p<0.001). Conclusions: DTI metrics, especially rFA deep WM, may be a surrogate marker of stroke age.Axonal damage in the CST revealed by DTI at day 30 is an independent predictor of long-term motor outcome after strok

Hypothalamic damage is associated with inflammatory markers and worse cognitive performance in obese subjects

Context: Growing evidence implicates hypothalamic inflammation in the pathogenesis of dietinduced obesity and cognitive dysfunction in rodent models. Few studies have addressed the association between obesity and hypothalamic damage in humans and its relevance. Objective: To determine markers of obesity-associated hypothalamic damage on diffusion tensor imaging (DTI) and to determine whether DTI-metrics are associated with performance on cognitive testing. Design and Participants: This cross-sectional study analyzed DTI-metrics (primary (λ1), secondary (λ2), and tertiary (λ3) eigenvalues; fractional anisotropy (FA); and mean diffusivity (MD)) in the hypothalamus of 24 consecutive middle-aged obese subjects (13 women; 49.8 ± 8.1 years; body mass index [BMI] 43.9 ± 0.92 Kg/m2) and 20 healthy volunteers (10 women; 48.8 ± 9.5 years; BMI 24.3 ± 0.79 Kg/m2). Outcome: measures: Hypothalamic damage assessed by DTI-metrics and cognitive performance evaluated by neuropsychological test-battery. Results: λ1 values in the hypothalamus were significantly lower in obese subjects (P<0.0001). The sensitivity, specificity, and positive and negative predictive values for obesity-associated hypothalamic damage by λ1<1.072 were 75%, 87.5%, 83.3%, and 80.7%, respectively. Patients with hypothalamic λ1<1.072 had higher values of BMI, fat mass, inflammatory markers, carotid-intima media thickness, and hepatic steatosis and lower scores on cognitive tests. Combined BMI and alanine aminotransferase had the strongest association with hypothalamic damage reflected by λ1<1.072 (AUC=0.89). Conclusions: DTI detects obesity-associated hypothalamic damage associated with inflammatory markers and worse cognitive performance. This study highlights the potential utility of λ1 as a surrogate marker of obesity-associated hypothalamic damag

Acute damage to the posterior limb of the internal capsule on diffusion tensor tractography as an early imaging predictor of motor outcome after stroke

BACKGROUND AND PURPOSE: Early prediction of motor outcome is of interest in stroke management. We aimed to determine whether lesion location at DTT is predictive of motor outcome after acute stroke and whether this information improves the predictive accuracy of the clinical scores. MATERIALS AND METHODS: We evaluated 60 consecutive patients within 12 hours of middle cerebral artery stroke onset. We used DTT to evaluate CST involvement in the motor cortex and premotor cortex, centrum semiovale, corona radiata, and PLIC and in combinations of these regions at admission, at day 3, and at day 30. Severity of limb weakness was assessed by using the motor subindex scores of the National Institutes of Health Stroke Scale (5a, 5b, 6a, 6b). We calculated volumes of infarct and fractional anisotropy values in the CST of the pons. RESULTS: Acute damage to the PLIC was the best predictor associated with poor motor outcome, axonal damage, and clinical severity at admission (P < .001). There was no significant correlation between acute infarct volume and motor outcome at day 90 (P = .176, r = 0.485). The sensitivity, specificity, and positive and negative predictive values of acute CST involvement at the level of the PLIC for motor outcome at day 90 were 73.7%, 100%, 100%, and 89.1%, respectively. In the acute stage, DTT predicted motor outcome at day 90 better than the clinical scores (R2 = 75.50, F = 80.09, P < .001). CONCLUSIONS: In the acute setting, DTT is promising for stroke mapping to predict motor outcome. Acute CST damage at the level of the PLIC is a significant predictor of unfavorable motor outcom

Intravoxel Incoherent Motion Metrics as Potential Biomarkers for Survival in Glioblastoma

Intravoxel incoherent motion (IVIM) is an MRI technique with potential applications in measuring brain tumor perfusion, but its clinical impact remains to be determined. We assessed the usefulness of IVIM-metrics in predicting survival in newly diagnosed glioblastoma. Methods Fifteen patients with glioblastoma underwent MRI including spin-echo echo-planar DWI using 13 b-values ranging from 0 to 1000 s/mm2. Parametric maps for diffusion coefficient (D), pseudodiffusion coefficient (D*), and perfusion fraction (f) were generated for contrast-enhancing regions (CER) and non-enhancing regions (NCER). Regions of interest were manually drawn in regions of maximum f and on the corresponding dynamic susceptibility contrast images. Prognostic factors were evaluated by Kaplan-Meier survival and Cox proportional hazards analyses. Results We found that fCER and D*CER correlated with rCBFCER. The best cutoffs for 6-month survival were fCER>9.86% and D*CER>21.712 x10−3mm2/s (100% sensitivity, 71.4% specificity, 100% and 80% positive predictive values, and 80% and 100% negative predictive values; AUC:0.893 and 0.857, respectively). Treatment yielded the highest hazard ratio (5.484; 95% CI: 1.162–25.88; AUC: 0.723; P = 0.031); fCER combined with treatment predicted survival with 100% accuracy. Conclusions The IVIM-metrics fCER and D*CER are promising biomarkers of 6-month survival in newly diagnosed glioblastom

Quantification of thrombus Hounsfield units on noncontrast CT predicts stroke subtype and early recanalization after intravenous recombinant tissue plasminogen activator

BACKGROUND AND PURPOSE: Little is known about the factors that determine recanalization after intravenous thrombolysis. We assessed the value of thrombus Hounsfield unit quantification as a predictive marker of stroke subtype and MCA recanalization after intravenous rtPA treatment. MATERIALS AND METHODS: NCCT scans and CTA were performed on patients with MCA acute stroke within 4.5 hours of symptom onset. Demographics, stroke severity, vessel hyperattenuation, occlusion site, thrombus length, and time to thrombolysis were recorded. Stroke origin was categorized as LAA, cardioembolic, or indeterminate according to TOAST criteria. Two blinded neuroradiologists calculated the Hounsfield unit values for the thrombus and contralateral MCA segment. We used ROC curves to determine the rHU cutoff point to discriminate patients with successful recanalization from those without. We assessed the accuracy (sensitivity, specificity, and positive and negative predictive values) of rHU in the prediction of recanalization. RESULTS: Of 87 consecutive patients, 45 received intravenous rtPA and only 15 (33.3%) patients had acute recanalization. rHU values and stroke mechanism were the highest predictive factors of recanalization. The Matthews correlation coefficient was highest for rHU (0.901). The sensitivity, specificity, and positive and negative predictive values for lack of recanalization after intravenous rtPA for rHU ≤ 1.382 were 100%, 86.67%, 93.75%, and 100%, respectively. LAA thrombi had lower rHU than cardioembolic and indeterminate stroke thrombi (P = .004). CONCLUSIONS: The Hounsfield unit thrombus measurement ratio can predict recanalization with intravenous rtPA and may have clinical utility for endovascular treatment decision making

Wallerian degeneration in the corticospinal tract evaluated by diffusion tensor imaging correlates with motor deficit 30 days after middle cerebral artery ischemic stroke

BACKGROUND AND PURPOSE: The quantification and clinical significance of WD in CSTs following supratentorial stroke are not well understood. We evaluated the anisotropy by using DTI and signalintensity changes on conventional MR imaging in the CST to determine whether these findings are correlated with limb motor deficit in patients with MCA ischemic stroke. MATERIALS AND METHODS: We studied 60 patients within 12 hours of stroke onset. At admission, day 3, and day 30 of evolution, patients underwent multimodal MR imaging, including DTI sequences. We assessed the severity of limb weakness by using the motor subindex scores (5a, 5b, 6a, 6b) of the m-NIHSS and established 3 groups: I (m-NIHSS scores of 0), II (m-NIHSS, 1-4), and III (m-NIHSS, 5-8). FA values and rFAs were measured on the affected and the unaffected CSTs in the pons. RESULTS: FA values for the CST were significantly lower on the affected side compared with the unaffected side only at day 30 (P < .001), and the rFA was significantly correlated with the motor deficit at day 30 (P < .001; r=-0.793). The sensitivity, specificity, and positive and negative predictive values for motor deficit by rFA < 0.925 were 95.2%, 94.9%, 90.9%, and 97.4%, respectively. CONCLUSIONS: WD in the CST revealed by DTI correlates with motor deficit 30 days after MCA ischemic stroke. This study highlights the utility of imaging follow-up at 30 days and the potential of DTI as a surrogate marker in clinical trial

The ins and outs of the BCCAo model for chronic hypoperfusion: a multimodal and longitudinal MRI approach

Cerebral hypoperfusion induced by bilateral common carotid artery occlusion (BCCAo) in rodents has been proposed as an experimental model of white matter damage and vascular dementia. However, the histopathological and behavioral alterations reported in this model are variable and a full characterization of the dynamic alterations is not available. Here we implemented a longitudinal multimodal magnetic resonance imaging (MRI) design, including timeof- flight angiography, high resolution T1-weighted images, T2 relaxometry mapping, diffusion tensor imaging, and cerebral blood flow measurements up to 12 weeks after BCCAo or sham-operation in Wistar rats. Changes in MRI were related to behavioral performance in executive function tasks and histopathological alterations in the same animals. MRI frequently (70%) showed various degrees of acute ischemic lesions, ranging from very small to large subcortical infarctions. Independently, delayed MRI changes were also apparent. The patterns of MRI alterations were related to either ischemic necrosis or gliosis. Progressive microstructural changes revealed by diffusion tensor imaging in white matter were confirmed by observation of myelinated fiber degeneration, including severe optic tract degeneration. The latter interfered with the visually cued learning paradigms used to test executive functions. Independently of brain damage, BCCAo induced progressive arteriogenesis in the vertebrobasilar tree, a process that was associated with blood flow recovery after 12 weeks. The structural alterations found in the basilar artery were compatible with compensatory adaptive changes driven by shear stress. In summary, BCCAo in rats induces specific signatures in multimodal MRI that are compatible with various types of histological lesion and with marked adaptive arteriogenesi

Early and delayed infarct growth in patients undergoing mechanical thrombectomy: a prospective, serial MRI study

BACKGROUND: We studied the evolution over time of diffusion weighted imaging (DWI) lesion volume and the factors involved on early and late infarct growth (EIG and LIG) in stroke patients undergoing endovascular treatment (EVT) according to the final revascularization grade. METHODS: This is a prospective cohort of patients with anterior large artery occlusion undergoing EVT arriving at 1 comprehensive stroke center. Magnetic resonance imaging was performed on arrival (pre-EVT), <2 hours after EVT (post-EVT), and on day 5. DWI lesions and perfusion maps were evaluated. Arterial revascularization was assessed according to the modified Thrombolysis in Cerebral Infarction (mTICI) grades. We recorded National Institutes of Health Stroke Scale at arrival and at day 7. EIG was defined as (DWI volume post-EVT–DWI volume pre-EVT), and LIG was defined as (DWI volume at 5d–DWI volume post-EVT). Factors involved in EIG and LIG were tested via multivariable lineal models. RESULTS: We included 98 patients (mean age 70, median National Institutes of Health Stroke Scale score 17, final mTICI=2b 86%). Median EIG and LIG were 48 and 63.3 mL in patients with final mTICI<2b, and 3.6 and 3.9 cc in patients with final mTICI=2b. Both EIG and LIG were associated with higher National Institutes of Health Stroke Scale at day 7 (¿=0.667; P<0.01 and ¿=0.614; P<0.01, respectively). In patients with final mTICI=2b, each 10% increase in the volume of DWI pre-EVT and each extra pass leaded to growths of 9% (95% CI, 7%–10%) and 14% (95% CI, 2%–28%) in the DWI volume post-EVT, respectively. Furthermore, each 10% increase in the volume of DWI post-EVT, each extra pass, and each 10 mL increase in TMax6s post-EVT were associated with growths of 8% (95% CI, 6%–9%), 9% (95% CI, 0%–19%), and 12% (95% CI, 5%–20%) in the volume of DWI post-EVT, respectively. CONCLUSIONS: Infarct grows during and after EVT, especially in nonrecanalizers but also to a lesser extent in recanalizers. In recanalizers, number of passes and DWI volume influence EIG, while number of passes, DWI, and hypoperfused volume after the procedure determine LIG.Postprint (author's final draft

Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data

Background: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers. Methods: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0–1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0–2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4–6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903. Findings: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10–2·03]; p=0·011), with low heterogeneity across studies (I 2=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05–1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06–2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4–6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52–1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03–4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [<1%], adjusted OR 5·58 [1·22–25·50]; p=0·024). Interpretation: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death. Funding: None