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1.  Intervention versus standard medical treatment in patients with symptomatic occlusion of the internal carotid artery: a randomised oxygen-15 PET study 
EJNMMI Research  2013;3:79.
The aim of this randomised pilot study was to investigate the haemodynamic effects measured by oxygen-15 positron emission tomography (PET) of interventional treatment consisting of either endarterectomy or endovascular treatment of stenosed cerebropetal arteries, or tapering of antihypertensive medication in comparison with standard medical treatment alone in patients with symptomatic internal carotid artery (ICA) occlusion.
Twenty-three patients with symptomatic ICA occlusion underwent PET scanning at baseline and after 3 months. Twelve patients were randomised to intervention (either endarterectomy or endovascular treatment of stenosed cerebropetal arteries, or tapering of antihypertensive medication) and 11 to standard medical treatment alone. Primary outcome was a change in cerebral blood flow (CBF), cerebral blood volume (CBV) and/or oxygen extraction fraction (OEF) after 3 months measured by PET.
There were no differences in changes in CBF, CBV or OEF between the two groups. Only patients with compromised perfusion at presentation showed a borderline significant increase in CBF of 2.8 mL/min/100 mL (95% confidence interval 0.0 to 5.7) after intervention (n = 7).
This pilot study shows that in patients with symptomatic ICA occlusion, oxygen-15 PET did not detect differences in improvement of CBF, CBV or OEF between interventional and standard treatment.
PMCID: PMC4029781  PMID: 24308868
Carotid artery diseases; Haemodynamics; Other cerebrovascular disease/stroke; PET
2.  Amyloid imaging in clinical trials 
The possibility to map amyloid-beta, the Alzheimer’s disease hallmark protein, in vivo opens the application for amyloid imaging in clinical trials with disease-modifying agents. Monitoring change in amyloid burden, particularly when potential amyloid-lowering drugs are at play, requires accurate analytical methods. Studies to date have used suboptimal methods that do not account for heterogeneous changes in flow associated with disease progression and potentially with anti-amyloid drugs. In this commentary, we discuss practical and methodological issues regarding longitudinal amyloid imaging and propose several quantitative, yet feasible, alternatives for reliable assessment of changes over time in amyloid burden.
PMCID: PMC3978734  PMID: 23953396
3.  No evidence for additional blood–brain barrier P-glycoprotein dysfunction in Alzheimer's disease patients with microbleeds 
Decreased blood–brain barrier P-glycoprotein (Pgp) function has been shown in Alzheimer's disease (AD) patients using positron emission tomography (PET) with the radiotracer (R)-[11C]verapamil. Decreased Pgp function has also been hypothesized to promote cerebral amyloid angiopathy (CAA) development. Here, we used PET and (R)-[11C]verapamil to assess Pgp function in eighteen AD patients, of which six had microbleeds (MBs), presumably reflecting underlying CAA. No differences were found in binding potential and nonspecific volume of distribution of (R)-[11C]verapamil between patient groups. These results provide no evidence for additional Pgp dysfunction in AD patients with MBs.
PMCID: PMC3421102  PMID: 22588188
Alzheimer's disease; blood–brain barrier; cerebral amyloid angiopathy; P-glycoprotein; positron emission tomography; (R)-[11C]verapamil
4.  Optimization of supervised cluster analysis for extracting reference tissue input curves in (R)-[11C]PK11195 brain PET studies 
Performance of two supervised cluster analysis (SVCA) algorithms for extracting reference tissue curves was evaluated to improve quantification of dynamic (R)-[11C]PK11195 brain positron emission tomography (PET) studies. Reference tissues were extracted from images using both a manually defined cerebellum and SVCA algorithms based on either four (SVCA4) or six (SVCA6) kinetic classes. Data from controls, mild cognitive impairment patients, and patients with Alzheimer's disease were analyzed using various kinetic models including plasma input, the simplified reference tissue model (RPM) and RPM with vascular correction (RPMVb). In all subject groups, SVCA-based reference tissue curves showed lower blood volume fractions (Vb) and volume of distributions than those based on cerebellum time-activity curve. Probably resulting from the presence of specific signal from the vessel walls that contains in normal condition a significant concentration of the 18 kDa translocation protein. Best contrast between subject groups was seen using SVCA4-based reference tissues as the result of a lower number of kinetic classes and the prior removal of extracerebral tissues. In addition, incorporation of Vb in RPM improved both parametric images and binding potential contrast between groups. Incorporation of Vb within RPM, together with SVCA4, appears to be the method of choice for analyzing cerebral (R)-[11C]PK11195 neurodegeneration studies.
PMCID: PMC3421099  PMID: 22588187
clustering; parametric analysis; (R)-[11C]PK11195; reference tissue
5.  Amyloid imaging in prodromal Alzheimer's disease 
Patients with mild cognitive impairment are at an increased risk of progression to Alzheimer's disease. However, not all patients with mild cognitive impairment progress, and it is difficult to accurately identify those patients who are in the prodromal stage of Alzheimer's disease. In a recent paper, Koivunen and colleagues report that Pittsburgh compound-B, an amyloid-beta positron emission tomography ligand, predicts the progression of patients with mild cognitive impairment to Alzheimer's disease. Of 29 subjects with mild cognitive impairment, 21 (72%) had a positive Pittsburgh compound-B positron emission tomography baseline scan. In their study, 15 of these 21 (71%) patients progressed to Alzheimer's disease, whilst only 1 out of 8 (12.5%) Pittsburgh compound-B-negative patients with mild cognitive impairment did so. Moreover, in these mild cognitive impairment patients, the overall amyloid burden increased approximately 2.5% during the follow-up period. This is consistent with other longitudinal amyloid imaging studies that found a similar increase in amyloid deposition over time in patients with mild cognitive impairment. These studies together challenge current theories that propose a flattening of the increase of brain amyloid deposition already in the preclinical stage of Alzheimer's disease. These findings may have important implications for the design of future clinical trials aimed at preventing progression to Alzheimer's disease by lowering the brain amyloid-beta burden in patients with mild cognitive impairment.
PMCID: PMC3218803  PMID: 21936965
6.  Reproducibility of quantitative (R)-[11C]verapamil studies 
EJNMMI Research  2012;2:1.
P-glycoprotein [Pgp] dysfunction may be involved in neurodegenerative diseases, such as Alzheimer's disease, and in drug resistant epilepsy. Positron emission tomography using the Pgp substrate tracer (R)-[11C]verapamil enables in vivo quantification of Pgp function at the human blood-brain barrier. Knowledge of test-retest variability is important for assessing changes over time or after treatment with disease-modifying drugs. The purpose of this study was to assess reproducibility of several tracer kinetic models used for analysis of (R)-[11C]verapamil data.
Dynamic (R)-[11C]verapamil scans with arterial sampling were performed twice on the same day in 13 healthy controls. Data were reconstructed using both filtered back projection [FBP] and partial volume corrected ordered subset expectation maximization [PVC OSEM]. All data were analysed using single-tissue and two-tissue compartment models. Global and regional test-retest variability was determined for various outcome measures.
Analysis using the Akaike information criterion showed that a constrained two-tissue compartment model provided the best fits to the data. Global test-retest variability of the volume of distribution was comparable for single-tissue (6%) and constrained two-tissue (9%) compartment models. Using a single-tissue compartment model covering the first 10 min of data yielded acceptable global test-retest variability (9%) for the outcome measure K1. Test-retest variability of binding potential derived from the constrained two-tissue compartment model was less robust, but still acceptable (22%). Test-retest variability was comparable for PVC OSEM and FBP reconstructed data.
The model of choice for analysing (R)-[11C]verapamil data is a constrained two-tissue compartment model.
PMCID: PMC3274480  PMID: 22251281
Positron emission tomography; P-glycoprotein; reproducibility; (R)-[11C]verapamil
7.  Increased cerebral (R)-[11C]PK11195 uptake and glutamate release in a rat model of traumatic brain injury: a longitudinal pilot study 
The aim of the present study was to investigate microglia activation over time following traumatic brain injury (TBI) and to relate these findings to glutamate release.
Sequential dynamic (R)-[11C]PK11195 PET scans were performed in rats 24 hours before (baseline), and one and ten days after TBI using controlled cortical impact, or a sham procedure. Extracellular fluid (ECF) glutamate concentrations were measured using cerebral microdialysis. Brains were processed for histopathology and (immuno)-histochemistry.
Ten days after TBI, (R)-[11C]PK11195 binding was significantly increased in TBI rats compared with both baseline values and sham controls (p < 0.05). ECF glutamate values were increased immediately after TBI (27.6 ± 14.0 μmol·L-1) as compared with the sham procedure (6.4 ± 3.6 μmol·L-1). Significant differences were found between TBI and sham for ED-1, OX-6, GFAP, Perl's, and Fluoro-Jade B.
Increased cerebral uptake of (R)-[11C]PK11195 ten days after TBI points to prolonged and ongoing activation of microglia. This activation followed a significant acute posttraumatic increase in ECF glutamate levels.
PMCID: PMC3132713  PMID: 21672189
8.  In vivo validation of reconstruction-based resolution recovery for human brain studies 
The aim of this study was to validate in vivo the accuracy of a reconstruction-based partial volume correction (PVC), which takes into account the point spread function of the imaging system. The NEMA NU2 Image Quality phantom and five healthy volunteers (using [11C]flumazenil) were scanned on both HR+ and high-resolution research tomograph (HRRT) scanners. HR+ data were reconstructed using normalization and attenuation-weighted ordered subsets expectation maximization (NAW-OSEM) and a PVC algorithm (PVC-NAW-OSEM). HRRT data were reconstructed using 3D ordinary Poisson OSEM (OP-OSEM) and a PVC algorithm (PVC-OP-OSEM). For clinical studies, parametric volume of distribution (VT) images were generated. For phantom data, good recovery was found for both OP-OSEM (0.84 to 0.97) and PVC-OP-OSEM (0.91 to 0.98) HRRT reconstructions. In addition, for the HR+, good recovery was found for PVC-NAW-OSEM (0.84 to 0.94), corresponding well with OP-OSEM. Finally, for clinical data, good correspondence was found between PVC-NAW-OSEM and OP-OSEM-derived VT values (slope: 1.02±0.08). This study showed that HR+ image resolution using PVC-NAW-OSEM was comparable to that of the HRRT scanner. As the HRRT has a higher intrinsic resolution, this agreement validates reconstruction-based PVC as a means of improving the spatial resolution of the HR+ scanner and thereby improving the quantitative accuracy of positron emission tomography.
PMCID: PMC2949117  PMID: 19844240
high-resolution PET; high-resolution research tomograph; HRRT; PET; reconstruction-based partial volume correction; resolution recovery
9.  Arterial spin labeling perfusion MRI at multiple delay times: a correlative study with H215O positron emission tomography in patients with symptomatic carotid artery occlusion 
Arterial spin labeling (ASL) perfusion magnetic resonance imaging (MRI) with image acquisition at multiple inversion times is a noninvasive ASL technique able to compensate for spatial heterogeneities in transit times caused by collateral blood flow in patients with severe stenosis of the cerebropetal blood vessels. Our aim was to compare ASL-MRI and H215O positron emission tomography (PET), the gold standard for cerebral blood flow (CBF) assessment, in patients with a symptomatic internal carotid artery (ICA) occlusion. Fourteen patients (63±14 years) with a symptomatic ICA occlusion underwent both ASL-MRI and H215O PET. The ASL-MRI was performed using a pulsed STAR labeling technique at multiple inversion times within 7 days of the PET. The CBF was measured in the gray-matter of the anterior, middle and posterior cerebral artery, and white-matter. Both PET and ASL-MRI showed a significantly decreased CBF in the gray-matter of the middle cerebral artery in the hemisphere ipsilateral to the ICA occlusion. The average gray-matter CBF measured with ASL-MRI (71.8±4.3 mL/min/100 g) was higher (P<0.01) than measured with H215O PET (43.1±1.0 mL/min/100 g). In conclusion, ASL-MRI at multiple TIs is capable of depicting areas of regions with low CBF in patients with an occlusion of the ICA, although a systematic overestimation of CBF relative to H215O PET was noted.
PMCID: PMC2949108  PMID: 19809464
carotid artery; magnetic resonance imaging (MRI); MRI comparison with PET; MRI perfusion; positron emission tomography (PET)
10.  Blood–brain barrier P-glycoprotein function in healthy subjects and Alzheimer's disease patients: effect of polymorphisms in the ABCB1 gene 
EJNMMI Research  2012;2:57.
P-glycoprotein is a blood–brain barrier efflux transporter involved in the clearance of amyloid-beta from the brain and, as such, might be involved in the pathogenesis of Alzheimer's disease. P-glycoprotein is encoded by the highly polymorphic ABCB1 gene. Single-nucleotide polymorphisms in the ABCB1 gene have been associated with altered P-glycoprotein expression and function. P-glycoprotein function at the blood–brain barrier can be quantified in vivo using the P-glycoprotein substrate tracer (R)-[11C]verapamil and positron emission tomography (PET). The purpose of this study was to assess the effects of C1236T, G2677T/A and C3435T single-nucleotide polymorphisms in ABCB1 on blood–brain barrier P-glycoprotein function in healthy subjects and patients with Alzheimer's disease.
Thirty-two healthy subjects and seventeen patients with Alzheimer's disease underwent 60-min dynamic (R)-[11C]verapamil PET scans. The binding potential of (R)-[11C]verapamil was assessed using a previously validated constrained two-tissue plasma input compartment model and used as outcome measure. DNA was isolated from frozen blood samples and C1236T, G2677T/A and C3435T single-nucleotide polymorphisms were amplified by polymerase chain reaction.
In healthy controls, binding potential did not differ between subjects without and with one or more T present in C1236T, G2677T and C3435T. In contrast, patients with Alzheimer's disease with one or more T in C1236T, G2677T and C3435T had significantly higher binding potential values than patients without a T. In addition, there was a relationship between binding potential and T dose in C1236T and G2677T.
In Alzheimer's disease patients, C1236T, G2677T/A and C3435T single-nucleotide polymorphisms may be related to changes in P-glycoprotein function at the blood–brain barrier. As such, genetic variations in ABCB1 might contribute to the progression of amyloid-beta deposition in the brain.
PMCID: PMC3483228  PMID: 23067778
Blood–brain barrier; P-glycoprotein; ABCB1; MDR1; Polymorphisms; (R)-[11C]verapamil; PET

Results 1-10 (10)