ORIGINAL ARTICLE Improvement of Cerebral Glucose Metabolism in Symptomatic Patients With Carotid Artery Stenosis After Stenting Hsien-Li Kao, MD,* Mao-Shin Lin, MD,* Wen-Chau Wu, PhD,†‡ Wen-Yih I. Tseng, MD, PhD,† Mao-Yuan Su, PhD,† Ya-Fang Chen, MD,† Ming-Jang Chiu, MD,§ Shan-Ying Wang, MD,|| Wei-Shiung Yang, MD, PhD,* Kai-Yuan Tzen, MD,¶ Yen-Wen Wu, MD, PhD,*||¶#** and Ming-Fong Chen, MD, PhD* Purpose: Neurocognitive performance among patients with carotid artery stenosis or occlusion may deteriorate because of chronic cerebral hypoperfusion. Carotid artery stenting (CAS) has been reported to improve cerebral perfusion and neurocognitive function. The purpose of the study was to evaluate cerebral metabolism using 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) after CAS. Methods: Nineteen consecutive patients (15 men, 69 ± 13 years) with carotid artery stenosis or occlusion and cerebral ischemia detected on brain perfusion computed tomography (CT) or magnetic resonance imaging (MRI) were enrolled. Four patients had bilateral lesions, and 15 subjects had previous ischemic stroke. Neurocognitive function (NCF) assessments and brain FDG PET scans were performed before and 19 ± 7 (12–31) months after the procedure. Results: The procedural success rate of CAS was 70%. Two patients were excluded from the study because of procedural complications. No new cerebral ischemic events or neurologic deaths occurred during follow-up of 44 ± 11 (15–54) months. Significant improvements were observed in the Mini-Mental State Examination (before, 26.06 ± 3.32 versus after, 28.13 ± 2.8; P = 0.0016), the verbal fluency test (26.81 ± 7.82 versus 30.75 ± 9.58; P = 0.0378), and marginal upgrading in the Alzheimer Disease Assessment Scale–Cognitive Subtest (7.19 ± 7.59 versus 5.63 ± 5.90; P = 0.0523). Six of 9 patients who underwent successful CAS showed improvement of cerebral glucose metabolism. Of the 4 patients with recanalization failure, 2 exhibited decline in ipsilateral glucose metabolism. Cerebral FDG metabolism improved in patients with successful CAS (P = 0.038), although there was a weak correlation between interval change of NCF tests and brain FDG metabolism. Conclusions: Successful CAS may improve long-term cerebral glucose metabolism and neurocognitive function in patients with chronic severe carotid stenosis or occlusion. Received for publication October 23, 2014; revision accepted April 30, 2015. From the Departments of *Internal Medicine, †Medical Imaging, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei; ‡Graduate Institute of Oncology, National Taiwan University, Taipei; §Department of Neurology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei; ||Department of Nuclear Medicine, Far Eastern Memorial Hospital, New Taipei City; ¶Department of Nuclear Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei; #Department of Cardiology, Division of Cardiovascular Medical Center, Far Eastern Memorial Hospital, New Taipei City; **National YangMing University School of Medicine, Taipei, Taiwan, Republic of China. Conflict of interest and source of funding: The study was supported in parts by grants NSC 98-2314-B-002-145-MY2, 100-2314-B-002-158, and 1012314-B-418-012-MY3 from the National Science Council of Taiwan. The authors thank the staff of the National Taiwan University Hospital, Center for PET, and Advanced Biomedical MRI Lab for the assistance. H.-L.K. and M.-S.L contributed equally to this article. Correspondence to: Yen-Wen Wu, MD, PhD, Department of Nuclear Medicine, Far Eastern Memorial Hospital. No. 21, Sec. 2, Nanya S. Road., Banciao District, New Taipei City 220, Taiwan, Republic of China. E-mail: wuyw0502@gmail.com. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0363-9762/15/4009–0701 DOI: 10.1097/RLU.0000000000000880 Key Words: Carotid artery stenting, Perfusion, Cerebral metabolism, Positron emission tomography, Neurocognition (Clin Nucl Med 2015;40: 701–707) igh-grade carotid artery stenosis is a major risk factor for ischemic cerebral stroke. In addition, chronic cerebral hypoperfusion may lead to impairment in neurocognitive performance in patients with a chronic internal carotid artery stenosis or occlusion.1,2 Carotid artery stenting (CAS) and carotid endarterectomy have been reported to prevent stroke in patients with carotid artery stenosis.3–5 However, the effects of carotid revascularization on long-term neurocognitive outcome remain controversial because of potential confounding factors such as previous infarction, baseline cerebral perfusion, periprocedural embolism and temporary flow interruption, reperfusion injury, unstable hemodynamics postcarotid intervention, concurrent small vessel disease, and presence of other dementia disorders in the senile population.6–12 The feasibility and safety of endovascular recanalization of a carotid artery occlusion have been recently demonstrated.13,14 Indeed, patients who underwent successful CAS showed improvement in short-term neurocognitive function.15,16 Although improvement of cerebral perfusion is the most likely underlying mechanism,17,18 the sensitivity and specificity of imaging tools such as magnetic resonance imaging (MRI) or computed tomography (CT) are still insufficient to prove this relationship.19 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is a powerful tool for assessing brain metabolism in various dementia disorders, including microangiopathy.11,12,20 We hypothesized that FDG PET assessment of brain metabolism may be used in patients with chronic carotid total occlusion or severe stenosis, and that this technique would allow demonstration of a sustained metabolic improvement after successful CAS. H PATIENTS AND METHODS Inclusion Criteria We prospectively screened patients age 30 years or older with ultrasonographically documented carotid stenosis of 70% or greater who underwent elective angiography between October 2007 and September 2010. Patients with no evidence of cerebral ischemia according to brain perfusion CT or MRI were excluded. Other exclusion criteria included acute cerebral ischemic stroke within 1 month, cerebral hemorrhage within the past 6 months, vascular disease precluding catheter-based intervention, intracranial aneurysm or arteriovenous malformation, any major operation or bleeding within past 6 months, life expectancy of less than a year, educational level below elementary school, aphasia, right-sided hemiparesis, marked depression, at least moderate dementia, and failure to provide informed consent. At the time of enrollment, all patients had been receiving optimal medical therapy including aspirin, statin, and Clinical Nuclear Medicine • Volume 40, Number 9, September 2015 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. www.nuclearmed.com 701 Clinical Nuclear Medicine • Volume 40, Number 9, September 2015 Kao et al constant dosage of diabetes or hypertension medications for a minimum of 3 months. Diagnostic cerebral angiography was performed via the femoral route. The definition of carotid lesions, premedication, and details of the interventional techniques have been described previously.13–16 Protection devices were used unless the operator was unable to introduce the device. Each patient was given 5000 IU of unfractionated heparin intravenously with an additional dose dependent on activated clotting time. Tsunami peripheral stents (Terumo, Tokyo, Japan), Carotid Wallstents (Boston Scientific, MA) or Driver stents (Medtronic Vascular, CA) were used. Procedural success was defined as final residual diameter stenosis of 20% or less, a thrombolysis in myocardial infarction (TIMI) grade 3 antegrade flow, and freedom from neurological complication. All patients were monitored overnight in the intensive care unit for changes in hemodynamic and neurologic status, during which time systolic blood pressure was maintained between 100 and 140 mmHg. Aspirin and clopidogrel were continued for at least 3 months after successful intervention. Periprocedural and follow-up neurological sequelae, intracranial hemorrhage, and death were recorded. Baseline brain FDG PET and perfusion (CT or MRI) images were obtained within a month before cerebral angiography. Follow-up perfusion study and carotid echo were performed 3 months after the index procedure, whereas FDG PETwas scheduled at least 1 year later. Complete neurological examinations, including the assessment of National Institutes of Health Stroke Scale (NIHSS) and Barthel index, were done by an independent neurologist within one month of the time of FDG PET studies. The protocol was approved by the institutional review board of National Taiwan University Hospital, and written informed consent was obtained from each patient before enrollment. MRI MRI was performed on a 3 T whole body system (Trio, Siemens, Erlangen, Germany) using the body coil transmitter and an 8-channel phased array receiver. For perfusion study, a bolus of Gd-DTPA (0.1 mmol/kg; Magnevist, Schering, Berlin, Germany) was intravenously injected via the left antecubital vein at a rate of 4 to 6 mL/s, followed by 15 mL of a saline chaser; then, perfusionweighted images were repeatedly acquired using a spin-echo echoplanar sequence with the following parameters: TR = 3990 ms, TE = 47 ms, matrix = 128  128, flip angle = 90°, 20 axial slices, slice thickness = 3.9 mm, in-plane resolution = 1.98  1.98 mm, and 50 measurements. A standard vasoreactive stress protocol using an intravenous administration of 1 g of acetazolamide (Diamox) was additionally performed in patients with symmetric blood flow, small regions of cortical hypotension, or hypoperfusion only at previous infarct areas. Brain perfusion scans taken at rest and 15 minutes postchallenge were compared.21,22 Diffusion-weighted MRI was used to assess acute and chronic ischemic stroke.23 After motion correction, MR signal intensity over time (S[t]) was converted to the concentration time curve (C[t]) on  apixel-wise 1 log SSðtÞ , where S0 basis using the following equation: C ðt Þ∝− TE was the mean signal before the arrival of contrast media. Cerebral blood volume (CBV) was calculated as the ratio of the area under parenchymal C(t) (Cp[t]) to the area under an arterial input function (Ca[t]) determined at the middle cerebral arteries. Cerebral blood flow (CBF) and mean transit time (MTT) were then calculated as CBF = [Cp(t) ⊗−1Ca(t)]t = o and MTT ¼ CBV CBF , respectively, where ⊗−1 was the deconvolution operator. Block-circulant deconvolution was adopted for its insensitivity to the arrival timing of the bolus.24 O CT CT angiography and brain CT Xe/perfusion (CTP) were performed at rest and 15 minutes after 1 g acetazolamide (Diamox) 702 www.nuclearmed.com infusion using a 64 detector-row multi-detector CT scanner (LightSpeed VCT, GE Healthcare) in standardized protocols. CTP data were analyzed separately offline at a workstation using specialized CT software (CT Perfusion 3, Advantage 4.2; GE Healthcare), and CBV, CBF, and MTT were calculated.14–17 Assessment of cerebral perfusion using a side-by-side comparison of brain perfusion images before and after the procedure was performed by 2 independent investigators who were blinded to clinical and angiographic outcomes. Localization of stroke and the reduction of blood flow to the cerebral hemisphere were assessed. The topographic perfusion pattern was categorized as follows: absence of asymmetry, watershed zones, and vascular territory hypoperfusion. The following grading system for qualitatively assessing brain perfusion of a region of interest was used: complete perfusion (0), hypoperfusion with preserved cerebral blood volume (i.e., decreased CBF, increased MTT, and normal or elevated CBV, 1) and, hypoperfusion without adequate blood volume (i.e., decreased CBV, 2). Postprocedure improvement in brain perfusion was defined as a minimum decrease of 1 categorical number in brain perfusion in the region of interest of either the resting or poststress scans.14–17 The structural MRI or CT images were also used for the segmentation of metabolic PET data. FDG PET Brain metabolism was measured using FDG PET. Patients were instructed to fast for at least 8 hours before the intravenous injection of 333–407 (9–11 mCi) MBq of FDG. Glucose-free oral hydration was permitted during the fast. Blood glucose was measured before tracer injection to ensure level of 150 mg/dL of FDG or less were injected. After injection, patients were kept lying comfortably. The patient’s eyes were open, ears were unoccluded, and ambient noise was kept to a minimum during the study. Patients were instructed not to apply urinary bladder catheterization, bowel preparation regimen, or oral muscle relaxants in our series. Scanning was initiated 45 minutes after the administration of FDG using an integrated PET/CT device (Discovery LS; GE Healthcare), which combined the Advance NXi PET scanner and a 16-slice helical CT scanner (LightSpeed Plus). The axes of both systems were mechanically aligned to coincide perfectly. First, noncontrast CT data were acquired with the following parameters: scan length = 15.4 cm, rotation time = 0.5 s, and total scan time = 19 s at 120 kV 80 mA. Subsequent PETwas acquired in the 2-dimensional mode, and emission counts were collected for 15 minutes. The entire intracranial volume, including the cerebellum, was included in the field of view. Matched CT and PET image were reconstructed with 3.27 mm slice intervals, slice thickness of 3.75 mm, and a CT and PET matrix size of 512  512 and 256  256, respectively. An iterative reconstruction and CT-based attenuation correction were used for the PET images. The PET and CT datasets were transferred to an independent, personal computer-based workstation (Xeleris; GE) via DICOM transfer, allowing the viewing of PET, CT, and fused PET/CT images in axial, coronal, and sagittal planes. The brain FDG regional activity was normalized to the medium pixel values of the cerebellum and smoothed using a Gaussian filter (full width at half maximum = 8 mm) for purposes of the voxelbased analysis. Although FDG PET images were acquired using radiologic convention, FDG PET reorientation to an anatomical position was automatically performed during SPM normalization. To quantitatively compare the results obtained in 2 separate exams of the sample subject, the images of the follow-up exam were coregistered to the images of the first examination using the Statistical Parametric Mapping software package (http://www.fil.ion.ucl.ac.uk/spm/) in a MATLAB environment (The MathWorks, Natick, MA). We used © 2015 Wolters Kluwer Health, Inc. All rights reserved. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Clinical Nuclear Medicine • Volume 40, Number 9, September 2015 levels of significance of 5% to detect the interval difference on a pixelto-pixel basis (red color: improvement, blue color: deterioration in the follow-up studies). Neurocognitive Function A battery of 5 cognitive function tests were evaluated by an independent clinical psychologist who was blinded to any clinical information in the following sequence. Global cognitive assessment included the Mini-Mental State Examination (MMSE)25,26 and Alzheimer Disease Assessment Scale–Cognitive subscale (ADAS),27,28 which measures several cognitive domains, including memory, orientation, language, and ideational and constructional praxis. Total scores range from 0 to 70, with higher scores indicating greater cognitive impairment. Relevant tasks included verbal fluency (category naming: fruits, vegetables, and fishes) and Color Trails Test Parts 1 and 2, which was used to replace the more educational-dependent conventional Trail Making Test.29,30 Tests were carried out in an equal environment for all subjects by performing the tests in a quiet room created only for the evaluation. The tests were usually completed within 30 to 40 minutes. The instructor would be given an option of suspending testing if the subject felt fatigued. Statistical Analysis All values were expressed as means ± SD. Comparisons between continuous and categorical variables were made using a Student t test and w2 analysis, respectively. An analysis of variance was used to test the significance of associations between 2 or more variables. To evaluate neurocognitive changes over time, difference scores were calculated by subtracting the baseline scores from the follow-up scores. We compared the difference scores and interval change of FDG PET from baseline. All analyses were performed using STATA (release 10.0; StataCorp LP) statistical software. All statistical tests were 2-sided, and P < 0.05 was considered statistically significant. RESULTS Figure 1 shows the patient flow. Nineteen consecutive patients (69 ± 13 years; range, 50–84) with significant carotid artery disease and cerebral ischemia detected on brain perfusion CT (n = 12) or MRI (n = 7) were recruited. Fifteen subjects (79%) had a previous ischemic stroke in CT or MRI images (4 with minor lacunae infarcts). Four subjects (21%) had bilateral significant carotid diseases, whereas another 5 (26%) and 10 subjects (53%) had disease of the right and left side, respectively. The baseline clinical characteristics are summarized in Table 1. Carotid Stenting Improves Cerebral FDG Metabolism TABLE 1. Baseline Characteristics of Subjects (n = 19) Characteristic Age, yr Male sex Hypertension Diabetes mellitus Hyperlipidemia Coronary artery disease Smoking Never Former Current Presenting symptoms at procedure Cerebrovascular disease Dizziness/syncope Asymmetry of blood pressure Unilateral stenosis/occlusion Left ICA lesions Right ICA lesions Bilateral ICA stenosis/occlusion Value 69.2 ± 13.2 15 15 7 10 16 (50–85) (79%) (79%) (37%) (53%) (84%) 13 4 2 (68%) (21%) (11%) 15 3 1 15 10 5 4 (79%) (16%) (5%) (79%) (66%) (34%) (21%) Values within parenthesis represent corresponding percentage or range. ICA indicates internal carotid artery. A total of 23 endovascular procedures were performed (6 tsunami stents, 15 carotid Wall stents, and 1 driver stents), with an overall procedural success rate of 70% (16/23). Two patients were excluded from further analysis because they experienced periprocedural complications with neurologic sequelae, including 1 spontaneous dissection and embolization of middle cerebral artery and 1 subarachnoid hemorrhage after stenting (both in the ipsilateral hemisphere). Another 5 procedural failures were attributed to the inability to cross the occlusion with a guidewire, whereas no clinical events occurred in patients; these patients were nevertheless included in the study. All patients remained neurologically intact and stroke-free during 44 ± 11 (15–54) months postdischarge follow-up. Two noncardiovascular mortalities (gallbladder cancer and pneumonia) occurred at 15 and 36 months after the index procedures. The 3-month follow-up CT or MRI revealed improvement in ipsilateral cerebral perfusion or flow reserve without any evidence of a new infarct in all patients with procedural success. Neurocognitive function tests and brain FDG PET scans performed before and 19 ± 7 FIGURE 1. Flow of patients through the study. CT indicates computed tomography; MRI, magnetic resonance imaging; FDG PET/CT, 18F-fluorodeoxyglucose positron emission tomography/CT. © 2015 Wolters Kluwer Health, Inc. All rights reserved. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. www.nuclearmed.com 703 Kao et al Clinical Nuclear Medicine • Volume 40, Number 9, September 2015 FIGURE 2. A, MR images acquired at baseline showed no prior infarction, normal resting cerebral blood flow (CBF), increased cerebral blood volume (CBV), and delayed mean transient time (MTT). B, CBF map showed reversible pontine ischemia caused by acetazolamide challenge. Three months after carotid stenting, the CBV, MTT, and CBP map returned to normal. (12–31) months after the procedure were compared. All stents remained patent ultrasonographically at the postprocedure examination. The representative images of MR and PET of a 65-yearold woman with episodic transient ischemic accident had total occlusion of the left internal carotid artery are shown in Figures 2 and 3, respectively. Tables 2 and 3 show the changes of the FDG PET, neurocognitive, and neurological functions between baseline and follow-up. FDG-PET studies showed varying degrees of reduced glucose utilization in the stroke or ischemic regions. None had crossed cerebellar diaschisis before and after intervention. Interval changes in regional glucose metabolism between baseline and follow-up FDG PET scans were mainly in cortical areas (frontal, temporal, and parietal lobes) corresponding to the treated ICA territory. 704 www.nuclearmed.com Of the 13 patients with unilateral carotid disease, 9 were successfully stented, whereas 4 experienced recanalization failure. Six (66%) of nine stented patients showed improvement of cerebral glucose metabolism (two of each: ipsilateral, controlateral, and bilateral). Of the 4 patients with recanalization failure, 2 exhibited a decline in ipsilateral glucose metabolism, whereas the other 2 remained stationary. All 4 patients with bilateral disease showed improvement of cerebral glucose metabolism (two of each: unilateral and bilateral) after successful carotid stenting. Cerebral FDG metabolism improved at least one side in patients after successful CAS (P = 0.038). In neurocognitive and neurological function assessments, significant improvement in MMSE and verbal fluency test, and marginal upgrading in ADAS tests were noted, regardless of patient © 2015 Wolters Kluwer Health, Inc. All rights reserved. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Clinical Nuclear Medicine • Volume 40, Number 9, September 2015 Carotid Stenting Improves Cerebral FDG Metabolism FIGURE 3. FDG PET showed increased glucose uptake and metabolism in the bilateral frontal regions 14 months after successful stenting. age. In the analysis according to the affected side, patients with successful revascularization of the left carotid artery revealed a trend toward improved language functions (verbal fluency test +4.87 ± 6.31, P = 0.132). We did not compare individual NCF performance to the FDG metabolic activity in different locations because of case heterogeneity. However, when we specifically investigated the individual NCF test, there was no statistical correlation between NCF difference scores and the degree of interval change of brain FDG metabolism. DISCUSSION The current treatment goal of carotid atherosclerotic disease is stroke risk reduction. Carotid endarterectomy and CAS have both been proven to reduce future risk of embolic stroke.3–5,30,31 Theoretically, critical carotid narrowing may also cause cerebral hypoperfusion and functional disturbance, which may be reversible. Many lines of evidence suggest an association between carotid stenosis and neurocognitive dysfunction.2 Although improvement in neurocognitive function after revascularization may be expected based on improved hemodynamics, the actual effects of CAS and carotid endarterectomy on cognition remain controversial. We previously reported improvement in neurocognitive function within 3 months of successful CAS in patients with chronic carotid artery occlusion15 and asymptomatic patients with critical stenosis.16 We observed that the neurocognitive improvement after CAS was associated with the restoration of cerebral perfusion.17 In the present study, we further demonstrated long-term cerebral metabolic improvement after successful CAS in patients with cerebral perfusion deficits at baseline. To the best of our knowledge, this is the first study to evaluate the brain metabolic change using FDG PET in patients undergoing carotid revascularization. Many factors can explain the conflicting results of carotid revascularization on neurocognitive outcomes in previous studies, including patient factors (previous infarction, baseline cerebral perfusion status, concurrent small vessel disease, and other dementia disorders) and procedural factors (embolism and temporary flow interruption, reperfusion injury, and hemodynamic instability during/ after intervention).6–12 Another potential confounder between studies is the variable method of assessing neurocognitive function. Although neuropsychological tests are regarded as good measures of cognition, these tests largely measure global performance rather than focal function. Specific neuropsychiatric deficits and/or improvements may not be registered by these tests. Handedness may also affect the interpretation of test results. In addition, criteria for defining interval change in a neuropsychological test can vary. Although imaging tools such as functional MRI may be of potential importance in this regard, a standard protocol is lacking. FDG PET is a very sensitive and specific tool for assessing global and focal cerebral metabolism.20,32 In the present study, patients who underwent successful CAS had superior brain metabolism outcomes in comparison to those with recanalization failure. © 2015 Wolters Kluwer Health, Inc. All rights reserved. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. www.nuclearmed.com 705 Clinical Nuclear Medicine • Volume 40, Number 9, September 2015 Kao et al TABLE 2. Change in Brain FDG Metabolism Between Baseline and Follow-up No. PET F/U (mo) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 13 32 12 12 12 14 15 31 14 13 30 22 27 21 19 20 19 18 14 Previous Infarct Location Carotid Angiography L. LICA (CTO) RICAS (CS) B. basal ganglia, L. thalamus RICA (CTO) R. frontal, lacune RICA (CTO) RICAS (CS) LICA (CS) L. LICA (CTO) L. LICA (CTO) B. frontal, R. parietal RICAS (CS) B. thalamus/basal ganglia LICA (CTO) LICA (CS) L. parietal, R. P-O, lacune LICA (CTO) L. LICA (CS) RICAS (CS) L. internal capsule LICAS (CS) RICAS (CS) L. RICAS (CS) LICA (CTO) L. LICA (CS) LICA (CTO) RICA (CS) L. thalamus LICA (CTO) LICA (CS) PTA Side PTA Success (L/R) R/L R R R L L L R L L L R/L R/L R/L L L R L L Yes/yes No No Yes No No Yes Yes Yes Yes No Yes/yes Yes/yes Yes/no Yes No Yes Yes Yes Metabolism Adverse Event L No change Improve Improve No change Left MCA dissection No change No change No change No change Improve Improve No change Improve Improve No change Improve SAH No change Improve No change R Improve Improve Improve No change Deteriorate No change Deteriorate Improve No change No change No change Improve Improve Improve Improve Deteriorate No change Improve PET indicates positron emission tomography; F/U, follow-up; L, left; R, right; P-O, parieto-occipital; ICA, internal carotid artery; CS, critical stenosis; CTO, chronic total occlusion; PTA, percutaneous transluminal angioplasty; SAH, subarachnoid hemorrhage. The improvement of brain FDG observed in areas corresponding to the treated ICA territory could result from the restored perfusion. Interestingly, it was common to observe some degree of improvement in the contralateral hemisphere. This latter observation may be explained by a redistribution of blood flow in the collateral systems involving Circle of Willis and other meningeal anastomoses, which were exhausted before reperfusion. Because of the concern over radiation exposure, FDG PET was not performed at 3 months postrecanalization. Although all subjects had restoration of cerebral perfusion by CT or MRI at 3 months after successful CAS, some subjects did not exhibit improvement in FDG PET at 1 year. The discrepancy between brain perfusion and glucose metabolism may be explained by permanent white matter injury induced by chronic cerebral hypoperfusion.12,33,34 Indeed, this notion may also explain the heterogenous neurocognitive improvement after CAS in previous studies.15–18,33–36 Although we did not TABLE 3. Neurological and Neurocognitive Function at Baseline and Late After Carotid Intervention (n = 17) Baseline NIHSS Barthel index MMSE ADAS Color trial test 1 Color trial test 2 Verbal fluency Follow-up 0.94 ± 2.04 (0–8) 0.83 ± 1.82 (0–7) 97.22 ± 7.71 (70–100) 98.33 ± 4.20 (85–100) 26.06 ± 3.32 (19–29) 28.13 ± 2.80 (22–30) 7.19 ± 7.59 (1–34) 7.19 ± 7.59 (1–25) 98.94 ± 63.66 (32–229) 77.81 ± 44.63 (17–180) 164.25 ± 92.84 (42–393) 138.31 ± 73.12 (31–328) 26.81 ± 7.82 (9–43) 30.75 ± 9.58 (13–52) P 0.3313 0.3313 0.0016 0.0523 0.0948 0.129 0.0378 Values are mean ± S.D (ranges). ADAS indicates Alzheimer Disease Assessment Scale; MMSE, Mini-Mental State Examination score; NIHSS, National Institutes of Health Stroke Scale. 706 www.nuclearmed.com perform a perfusion CT or MRI at the time of follow-up FDG PET scans, none of the subjects had in-stent restenosis according to ultrasound examination. However, progression of intracranial disease or microangiopathy cannot be excluded in these patients.37 More information is needed to explain this discrepancy. Larger prospective randomized studies are warranted.37–40 We confirmed that successful CAS improves NCF in patients with severe carotid stenosis or occlusion. However, despite the use of an extensive test battery that assessed the most consistently affected domains and tasks, we could not find a significant association between interval change of NCF and brain FDG metabolism. The nonsignificant correlation is most likely due to a small sample size. High prevalence of bilateral or left side diseases and previous infarcts may also affect the outcomes of NCF and cerebral glucose metabolism after successful recanalization. In addition, the brain perfusion and FDG metabolism were scored according to a semiquantitative rating scale. This simple scale is frequently used but has several shortcomings such as ceiling effects, lack of precision, and inadequate sensitivity, in contrast to automatic volumetric measurements. This study has a number of limitations. First, the natural temporal course of brain FDG metabolism in carotid artery stenosis or occlusion is unknown, and optimal timing of follow-up remains unclear. Second, the small sample size with heterogeneity and lack of randomization limited the interpretation of our data. Third, our study showed that overall successful recanalization rate was 70%, whereas the major cerebral complication rate was 9%, higher than literature reported, most likely because of a small sample size. Constant monitoring of the rate of periprocedural complications is important because outcomes depend mainly on the experience of the operators and appropriate patient selection. Finally, although FDG PET is a noninvasive tool widely used for measuring correlates of metabolic activity in the human brain, its use has mostly been limited to the cerebral cortex rather than the subcortical regions. Because the © 2015 Wolters Kluwer Health, Inc. All rights reserved. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Clinical Nuclear Medicine • Volume 40, Number 9, September 2015 PET technique has relatively lower spatial resolution than CTor MRI, it might not be able to clearly demonstrate the interval changes in metabolic activity of subcortical areas. Future studies with larger patient numbers (including patients with and without reperfusion abnormality) and longer follow-up periods are warranted. CONCLUSIONS Successful CAS improves neurocognitive function and cerebral glucose metabolism in patients with objectively assessed cerebral ischemia due to severe chronic carotid stenosis or occlusion. REFERENCES 1. 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