Accelerated high frequency rTMS induces time-dependent dopaminergic alterations: a DaTSCAN brain imaging study in healthy beagle dogs.

Aim: The neurobiological effects of repetitive transcranial magnetic stimulation are believed to run in part through the dopaminergic system. Accelerated high frequency rTMS (aHF-rTMS), a new form of stimuli delivery, is currently being tested for its usefulness in treating human and canine mental disorders. However, the short-and long-term neurobiological effects are still unclear, including the effects on the dopaminergic system. In aHF-rTMS, multiple sessions are delivered within 1 day instead of one session per day, not only to accelerate the time to response but also to increase clinical efficacy. To gain more insight into the neurobiology of aHF-rTMS, we investigated whether applying five sessions in 1 day has direct and/or delayed effects on the dopamine transporter (DAT), and on dopamine metabolites of cerebrospinal fluid (CSF) in beagles. Materials and methods: Thirteen beagles were randomly divided into two groups: five active stimulation sessions (n = 9), and 5 sham stimulation sessions (n = 4). Using DaTSCAN, DAT binding indices (BI) were obtained at baseline, after 1 day, 1 month, and 3 months post stimulation. CSF samples were collected after each scan. Results: Active aHF-rTMS significantly reduced striatal DAT BI 1 day post-active stimulation session (p < 0.01), and the effect lasted to 1 month (p < 0.01). No significant DAT BI change was found in sham group. No significant changes in dopamine metabolites of CSF were found. Conclusion: Although no significant effects on CSF dopamine metabolites were observed, five sessions of active aHF-rTMS significantly decreased striatal DAT BI after 1 day and up to 1 month post stimulation, indicating immediate and delayed effects on the brain dopaminergic system. Our findings in healthy beagles further substantiate the assumption that (a)HF-rTMS affects the brain dopaminergic system and it may pave the way to apply (a)HF-rTMS treatment in behaviorally disturbed dogs.

The Impact of Accelerated HF-rTMS on Canine Brain Metabolism: An [18F]-FDG PET Study in Healthy Beagles.

Background: Repetitive transcranial magnetic stimulation (rTMS) has been proven to be a useful tool for the treatment of several severe neuropsychiatric disorders. Accelerated (a)rTMS protocols may have the potential to result in faster clinical improvements, but the effects of such accelerated paradigms on brain function remain to be elucidated. Objectives: This sham-controlled arTMS study aimed to evaluate the immediate and delayed effects of accelerated high frequency rTMS (aHF-rTMS) on glucose metabolism in healthy beagle dogs when applied over the left frontal cortex. Methods: Twenty-four dogs were randomly divided into four unequal groups: five active (n = 8)/ sham (n = 4) stimulation sessions (five sessions in 1 day), 20 active (n = 8)/ sham (n = 4) stimulation sessions (five sessions/ day for 4 days), respectively. [18F] FDG PET scans were obtained at baseline, 24 h poststimulation, after 1 and 3 months post the last stimulation session. We explicitly focused on four predefined regions of interest (left/right prefrontal cortex and left/right hippocampus). Results: One day of active aHF-rTMS- and not sham- significantly increased glucose metabolism 24 h post-active stimulation in the left frontal cortex only. Four days of active aHF-rTMS only resulted in a nearly significant metabolic decrease in the left hippocampus after 1 month. Conclusions: Like in human psychiatric disorders, active aHF-rTMS in healthy beagles modifies glucose metabolism, although differently immediately or after 1 month post stimulation. aHF-rTMS may be also a valid option to treat mentally disordered dogs.

Accelerated HF-rTMS Modifies SERT Availability in the Subgenual Anterior Cingulate Cortex: A Canine [11C]DASB Study on the Serotonergic System.

Repetitive transcranial magnetic stimulation (rTMS) is thought to partly exert its antidepressant action through the serotonergic system. Accelerated rTMS may have the potential to result in similar but faster onset of clinical improvement compared to the classical daily rTMS protocols, but given that delayed clinical responses have been reported, the neurobiological effects of accelerated paradigms remain to be elucidated including on this neurotransmitter system. This sham-controlled study aimed to evaluate the effects of accelerated high frequency rTMS (aHF-rTMS) over the left frontal cortex on the serotonin transporter (SERT) in healthy beagle dogs. A total of twenty-two dogs were randomly divided into three unequal groups: five active stimulation sessions (five sessions in one day, n = 10), 20 active stimulation sessions (five sessions/day for four days, n = 8), and 20 sham stimulation sessions (five sessions/day for four days, n = 4). The SERT binding index (BI) was obtained at baseline, 24 h post stimulation protocol, one month, and three months post stimulation by a [11C]DASB PET scan. It was found that one day of active aHF-rTMS (five sessions) did not result in significant SERT BI changes at any time point. For the 20 sessions of active aHF-rTMS, one month after stimulation the SERT BI attenuated in the sgACC. No significant SERT BI changes were found after 20 sessions of sham aHF-rTMS. A total of four days of active aHF-rTMS modified sgACC SERT BI one month post-stimulation, explaining to some extent the delayed clinical effects of accelerated rTMS paradigms found in human psychopathologies.

Kinetic analysis of [18F] altanserin bolus injection in the canine brain using PET imaging.

BACKGROUND: Currently, [18F] altanserin is the most frequently used PET-radioligand for serotonin2A (5-HT2A) receptor imaging in the human brain but has never been validated in dogs. In vivo imaging of this receptor in the canine brain could improve diagnosis and therapy of several behavioural disorders in dogs. Furthermore, since dogs are considered as a valuable animal model for human psychiatric disorders, the ability to image this receptor in dogs could help to increase our understanding of the pathophysiology of these diseases. Therefore, five healthy laboratory beagles underwent a 90-min dynamic PET scan with arterial blood sampling after [18F] altanserin bolus injection. Compartmental modelling using metabolite corrected arterial input functions was compared with reference tissue modelling with the cerebellum as reference region. RESULTS: The distribution of [18F] altanserin in the canine brain corresponded well to the distribution of 5-HT2A receptors in human and rodent studies. The kinetics could be best described by a 2-Tissue compartment (2-TC) model. All reference tissue models were highly correlated with the 2-TC model, indicating compartmental modelling can be replaced by reference tissue models to avoid arterial blood sampling. CONCLUSIONS: This study demonstrates that [18F] altanserin PET is a reliable tool to visualize and quantify the 5-HT2A receptor in the canine brain.

PET quantification of [18F]MPPF in the canine brain using blood input and reference tissue modelling.

Numerous studies have shown that the serotonin1A (5-HT1A) receptor is implicated in the pathophysiology and treatment of several psychiatric and neurological disorders. Furthermore, functional imaging studies in a variety of species have demonstrated that 4-(2´-Methoxyphenyl)-1-[2´-(N-2´´-pyridinyl)-p- [18F]fluorobenzamidoethylpiperazine ([18F]MPPF) is a valid and useful PET tracer to visualize the 5HT1A receptor. However, to our knowledge, [18F]MPPF has never been demonstrated in the canine brain. The ability to image the 5HT1A receptor with PET in dogs could improve diagnosis and therapy in both canine and human behavioural and neuropsychiatric disorders. To examine the potential use of [18F]MPPF in dogs, five healthy adult laboratory beagles underwent a 60-minutes dynamic PET scan with [18F]MPPF while arterial blood samples were taken. For each region of interest, total distribution volume (VT) and corresponding binding potential (BPND) were calculated using the 1-tissue compartment model (1-TC), 2-Tissue compartment model (2-TC) and Logan plot. The preferred model was chosen based on the goodness-of-fit, calculated with the Akaike information criterium (AIC). Subsequently, the BPND values of the preferred compartment model were compared with the estimated BPND values using three reference tissue models (RTMs): the 2-step simplified reference tissue model (SRTM2), the 2-parameter multilinear reference tissue model (MRTM2) and the Logan reference tissue model. According to the lower AIC values of the 2-TC model compared to the 1-TC in all ROIs, the 2-TC model showed a better fit. Calculating BPND using reference tissue modelling demonstrated high correlation with the BPND obtained by metabolite corrected plasma input 2-TC. This first-in-dog study indicates the results of a bolus injection with [18F]MPPF in dogs are consistent with the observations presented in the literature for other animal species and humans. Furthermore, for future experiments, compartmental modelling using invasive blood sampling could be replaced by RTMs, using the cerebellum as reference region.

Estimation of the optimal dosing regimen of escitalopram in dogs: A dose occupancy study with [11C]DASB.

Although the favourable characteristics of escitalopram as being the most selective serotonin reuptake inhibitor and having an increased therapeutic efficacy via binding on an additional allosteric binding site of the serotonin transporter, its dosing regimen has not yet been optimized for its use in dogs. This study aimed to estimate the optimal dosing frequency and the required dose for achieving 80% occupancy of the serotonin transporters in the basal ganglia. The dosing frequency was investigated by determining the elimination half-life after a four day oral pre-treatment period with 0.83 mg/kg escitalopram (3 administrations/day) and a subsequent i.v. injection 0.83 mg/kg. Blood samples were taken up to 12 hours after i.v. injection and the concentration of escitalopram in plasma was analysed via LC-MSMS. The dose-occupancy relationship was then determined by performing two PET scans in five adult beagles: a baseline PET scan and a second scan after steady state conditions were achieved following oral treatment with a specific dose of escitalopram ranging from 0.5 to 2.5 mg/kg/day. As the elimination half-life was determined to be 6.7 hours a dosing frequency of three administrations a day was proposed for the second part of the study. Further it was opted for a treatment period of four days, which well exceeded the minimum period to achieve steady state conditions. The optimal dosing regimen to achieve 80% occupancy in the basal ganglia and elicit a therapeutic effect, was calculated to be 1.85 mg/kg/day, divided over three administrations. Under several circumstances, such as insufficient response to other SSRIs, concurrent drug intake or in research studies focused on SERT, the use of escitalopram can be preferred over the use of the already for veterinary use registered fluoxetine, however, in case of long-term treatment with escitalopram, regularly cardiac screening is recommended.

Evaluation of Feline Renal Perfusion with Contrast-Enhanced Ultrasonography and Scintigraphy.

Contrast-enhanced ultrasound (CEUS) is an emerging technique to evaluate tissue perfusion. Promising results have been obtained in the evaluation of renal perfusion in health and disease, both in human and veterinary medicine. Renal scintigraphy using 99mTc-Mercaptoacetyltriglycine (MAG3) is another non-invasive technique that can be used to evaluate renal perfusion. However, no data are available on the ability of CEUS or 99mTc- MAG3 scintigraphy to detect small changes in renal perfusion in cats. Therefore, both techniques were applied in a normal feline population to evaluate detection possibilities of perfusion changes by angiotensin II (AT II). Contrast-enhanced ultrasound using a bolus injection of commercially available contrast agent and renal scintigraphy using 99mTc-MAG3 were performed in 11 healthy cats after infusion of 0,9% NaCl (control) and AT II. Angiotensin II induced changes were noticed on several CEUS parameters. Mean peak enhancement, wash-in perfusion index and wash-out rate for the entire kidney decreased significantly after AT II infusion. Moreover, a tendency towards a lower wash-in area-under-the curve was present. Renal scintigraphy could not detect perfusion changes induced by AT II. This study shows that CEUS is able to detect changes in feline renal perfusion induced by AT II infusion.

In Vivo Evaluation of Blood Based and Reference Tissue Based PET Quantifications of [11C]DASB in the Canine Brain.

This first-in-dog study evaluates the use of the PET-radioligand [11C]DASB to image the density and availability of the serotonin transporter (SERT) in the canine brain. Imaging the serotonergic system could improve diagnosis and therapy of multiple canine behavioural disorders. Furthermore, as many similarities are reported between several human neuropsychiatric conditions and naturally occurring canine behavioural disorders, making this tracer available for use in dogs also provide researchers an interesting non-primate animal model to investigate human disorders. Five adult beagles underwent a 90 minutes dynamic PET scan and arterial whole blood was sampled throughout the scan. For each ROI, the distribution volume (VT), obtained via the one- and two- tissue compartment model (1-TC, 2-TC) and the Logan Plot, was calculated and the goodness-of-fit was evaluated by the Akaike Information Criterion (AIC). For the preferred compartmental model BPND values were estimated and compared with those derived by four reference tissue models: 4-parameter RTM, SRTM2, MRTM2 and the Logan reference tissue model. The 2-TC model indicated in 61% of the ROIs a better fit compared to the 1-TC model. The Logan plot produced almost identical VT values and can be used as an alternative. Compared with the 2-TC model, all investigated reference tissue models showed high correlations but small underestimations of the BPND-parameter. The highest correlation was achieved with the Logan reference tissue model (Y = 0.9266 x + 0.0257; R2 = 0.9722). Therefore, this model can be put forward as a non-invasive standard model for future PET-experiments with [11C]DASB in dogs.

Effect of thyroid volume on radioiodine therapy outcome in hyperthyroid cats.

Radioiodine therapy is commonly used in hyperthyroid cats and has a high success rate, ranging from 85-95%. As in humans, thyroid volume has been reported to influence radioiodine therapy outcome in hyperthyroid cats. The purpose of this study was to relate total thyroid volume, calculated by a newly constructed formula for feline patients (0.438 × length × width²), to the outcome of radioiodine therapy. To search for a correlation between total thyroid volume and therapy outcome, 167 hyperthyroid cats were included. Patients were categorised according to the administered radioiodine dose and therapy outcome. Our analysis did not show a significant relationship between an increasing total thyroid volume and the odds for a final low total thyroxine concentration (TT4; P = 0.3930) or a final hyperthyroid outcome (P = 0.0901). A significant relationship was found for an increase in the odds for a final low TT4 outcome with an increase in the number of foci detected on the pertechnetate thyroid scan (P = 0.0238). This was not true for a final hyperthyroid outcome (P = 0.7435). The number of detected foci was also significantly associated with the total thyroid volume (P = 0.0006). Findings indicated that the presence of multiple affected foci influences therapy outcome towards a low TT4 outcome. Bilateral hyperthyroidism and its potential effect on a final low TT4 outcome should therefore be addressed when informing owners of the possible outcomes of radioiodine therapy for their cat.

In vivo quantification of the [(11)C]DASB binding in the normal canine brain using positron emission tomography.

BACKGROUND: [(11)C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile ([(11)C]DASB) is currently the mostly used radiotracer for positron emission tomography (PET) quantitative studies of the serotonin transporter (SERT) in the human brain but has never been validated in dogs. The first objective was therefore to evaluate normal [(11)C]DASB distribution in different brain regions of healthy dogs using PET. The second objective was to provide less invasive and more convenient alternative methods to the arterial sampling-based kinetic analysis. RESULTS: A dynamic acquisition of the brain was performed during 90 min. The PET images were coregistered with the magnetic resonance images taken prior to the study in order to manually drawn 20 regions of interest (ROIs). The highest radioactivity concentration of [(11)C]DASB was observed in the hypothalamus, raphe nuclei and thalamus and lowest levels in the parietal cortex, occipital cortex and cerebellum. The regional radioactivity in those 20 ROIs was quantified using the multilinear reference tissue model 2 (MRTM2) and a semi-quantitative method. The values showed least variability between 40 and 60 min and this time interval was set as the optimal time interval for [(11)C]DASB quantification in the canine brain. The correlation (R(2)) between the MRTM2 and the semi-quantitative method using the data between 40 and 60 min was 99.3% (two-tailed p-value < 0.01). CONCLUSIONS: The reference tissue models and semi-quantitative method provide a more convenient alternative to invasive arterial sampling models in the evaluation of the SERT of the normal canine brain. The optimal time interval for static scanning is set at 40 to 60 min after tracer injection.

Comparison of the EANM and SNM guidelines on diuretic renography in children.

OBJECTIVE: When taking into account the Society of Nuclear Medicine (SNM) and European Association of Nuclear Medicine (EANM) guidelines on diuretic renography in children, we see important divergences in the preparation, acquisition, processing, and interpretation of the results. In this study, we estimated the quality of renal drainage according to these two guidelines. PATIENTS AND METHODS: Ninety kidneys with hydronephrosis or severe vesicorenal reflux were processed and analyzed according to the SNM (estimation of the T1/2 of the washout curve and conclusions about the possible existence of obstruction) and EANM guidelines (estimation of normalized residual activity or NORA, and output efficiency or OE on the late postmicturition images, without any conclusion about the possible existence of obstruction). Among the 90 kidneys, 39, 20, and 31 were considered to have normal, equivocal, or poor drainage (obstruction), respectively, when the SNM guidelines were used. RESULTS: All 39 kidneys with good drainage according to SNM were also considered as normal using the EANM guidelines. Among the 20 equivocal cases based on T1/2, concordance between the two guidelines was obtained in only 35 and 0% when using NORA and OE (OE was considered normal in all 20 cases), respectively. Among the 31 cases defined as obstructed by SNM, only five were classified as 'poor drainage' using NORA and no single case was classified thus using OE. CONCLUSION: This limited study demonstrates that the use of different guidelines can lead to different interpretations of the results. This is unacceptable, and an agreement between both pediatric task groups of the SNM and EANM is urgently required.

The effect of morphine on regional cerebral blood flow measured by 99mTc-ECD SPECT in dogs.

To gain insights into the working mechanism of morphine, regional cerebral blood flow (rCBF) patterns after morphine administration were assessed in dogs. In a randomized cross-over experimental study, rCBF was estimated with 99mTc-Ethylcysteinate Dimer single photon emission computed tomography in 8 dogs at baseline, at 30 minutes and at 120 minutes after a single bolus of morphine. Perfusion indices (PI) in the frontal, parietal, temporal and occipital cortex and in the subcortical and cerebellar region were calculated. PI was significantly decreased 30 min after morphine compared to baseline in the right frontal cortex. The left parietal cortex and subcortical region showed a significantly increased PI 30 min after morphine compared to baseline. No significant differences were noted for the other regions or at other time points. In conclusion, a single bolus of morphine generated a changing rCBF pattern at different time points.

Regional brain perfusion changes during standard and microburst vagus nerve stimulation in dogs.

PURPOSE: Vagus nerve stimulation (VNS) is an effective adjunctive treatment for refractory epilepsy in humans, but its mechanism of action (MOA) and optimal stimulation parameters are still unknown. Functional neuroimaging studies could provide better insight into the brain structures involved in the activity of VNS, but have not yet been described in dogs. The aim of this study was to investigate the effect of acute VNS on the regional cerebral blood flow (rCBF) in dogs using micro-SPECT (µ-SPECT). Additionally, a novel stimulation paradigm (microburst VNS) was used and compared with standard VNS. METHODS: A VNS Therapy System was implanted in ten Beagle dogs. µ-SPECT was performed after sham, standard and microburst VNS in a randomized, cross-over study. Nineteen volumes of interest (VOIs) were semi-quantitatively analysed and perfusion indices (PIs) were calculated. Furthermore, a rostro-caudal gradient (R-C), an asymmetry index (AI) and a cortical-subcortical index (Co-SCo) were determined. The SPECT results after standard and microburst VNS were compared pairwise with sham stimulation. RESULTS: Acute standard VNS did not cause significant rCBF alterations. Acute microburst VNS caused a significant hypoperfusion in the left frontal lobe (P=0.023) and in the right parietal lobe (P=0.035). Both stimulation paradigms did not cause changes in R-C, AI nor Co-SCo. CONCLUSIONS: Microburst VNS is more potent than standard VNS to modulate the rCBF in the dog. Our results promote further research towards the antiepileptic effect of microburst VNS in dogs and humans.

5-HT2A receptors in the feline brain: 123I-5-I-R91150 kinetics and the influence of ketamine measured with micro-SPECT.

UNLABELLED: Subanesthetic doses of ketamine can be used as a rapid-acting antidepressant in patients with treatment-resistant depression. Therefore, the brain kinetics of (123)I-5-I-R91150 (4-amino-N-[1-[3-(4-fluorophenyl)propyl]-4-methylpiperidin-4-yl]-5-iodo-2-methoxybenzamide) and the influence of ketamine on the postsynaptic serotonin-2A receptor (5-hydroxytryptamine-2A, or 5-HT2A) status were investigated in cats using micro-SPECT. METHODS: This study was conducted on 6 cats using the radioligand (123)I-5-I-R91150, a 5-HT2A receptor antagonist, as the imaging probe. Anesthesia was induced and maintained with a continuous-rate infusion of propofol (8.4 ± 1.2 mg kg(-1) followed by 0.22 mg kg(-1) min(-1)) 75 min after tracer administration, and acquisition of the first image began 15 min after induction of anesthesia. After this first acquisition, propofol (0.22 mg kg(-1) min(-1)) was combined with ketamine (5 mg kg(-1) followed by 0.023 mg kg(-1) min(-1)), and the second acquisition began 15 min later. Semiquantification, with the cerebellum as a reference region, was performed to calculate the 5-HT2A receptor binding indices (parameter for available receptor density) in the frontal and temporal cortices. The binding indices were analyzed with Wilcoxon signed ranks statistics. RESULTS: The addition of ketamine to the propofol continuous-rate infusion resulted in decreased binding indices in the right frontal cortex (1.25 ± 0.22 vs. 1.45 ± 0.16; P = 0.028), left frontal cortex (1.34 ± 0.15 vs. 1.49 ± 0.10; P = 0.028), right temporal cortex (1.30 ± 0.17 vs. 1.45 ± 0.09; P = 0.046), and left temporal cortex (1.41 ± 0.20 vs. 1.52 ± 0.20; P = 0.046). CONCLUSION: This study showed that cats can be used as an animal model for studying alterations of the 5-HT2A receptor status with (123)I-5-I-R91150 micro-SPECT. Furthermore, an interaction between ketamine and the 5-HT2A receptors resulting in decreased binding of (123)I-5-I-R91150 in the frontal and temporal cortices was demonstrated. Whether the decreased radioligand binding resulted from a direct competition between ketamine and (123)I-5-I-R91150 or from a decreased affinity of the 5-HT2A receptor caused by ketamine remains to be elucidated.

Normal regional distribution of cerebral blood flow in dogs: comparison between (99m) Tc-ethylcysteinate dimer and (99m) Tc- hexamethylpropylene amine oxime single photon emission computed tomography.

Functional imaging provides important insights into canine brain pathologies such as behavioral problems. Two (99m) Tc-labeled single photon emission computed tomography (SPECT) cerebral blood flow tracers-ethylcysteinate dimer (ECD) and hexamethylpropylene amine oxime (HMPAO)-are commonly used in human medicine and have been used previously in dogs but intrasubject comparison of both tracers in dogs is lacking. Therefore, this study investigated whether regional distribution differences between both tracers occur in dogs as is reported in humans. Eight beagles underwent two SPECT examinations first with (99m) Tc-ECD and followed by (99m) Tc-HMPAO. SPECT scanning was performed with a triple head gamma camera equipped with ultrahigh resolution parallel hole collimators. Images were reconstructed using filtered backprojection with a Butterworth filter. Emission data were fitted to a template permitting semiquantification using predefined regions or volumes of interest (VOIs). For each VOI, perfusion indices were calculated by normalizing the regional counts per voxel to total brain counts per voxel. The obtained perfusion indices for each region for both tracers were compared with a paired Student's T-test. Significant (P < 0.05) regional differences were seen in the subcortical region and the cerebellum. Both tracers can be used to visualize regional cerebral blood flow in dogs, however, due to the observed regional differences, they are not entirely interchangeable.

Effect of background region of interest and time-interval selection on glomerular filtration ratio estimation by percentage dose uptake of (99m)Tc-DTPA in comparison with (51)Cr-EDTA clearance in healthy cats.

Evaluation of glomerular function is a useful part of the diagnostic approach in animals suspected of having renal disease. Time-interval and background region of interest (bg ROI) selection are determining factors when calculating the glomerular filtration ratio (GFR) based on percentage uptake of (99m)technetium-labelled diethylene triamine penta-acetic acid ((99m)Tc-DTPA). Therefore, three different time intervals (60-120 s, 120-180 s, 60-180 s) and three different bg ROIs (C-shape, caudolateral, cranial + caudal) were investigated. In addition, global GFRs based on percentage dose uptake of (99m)Tc-DTPA for the different time-intervals and bg ROIs were compared with the global GFR based on (51)chromium-ethylene diaminic tetra-acetic acid ((51)Cr-EDTA) plasma clearance in nine healthy European domestic shorthair cats. Paired Student's t-tests and linear regression analysis were used to analyse the data. Different time intervals seemed to cause significant variation (P <0.01) in absolute GFR values, regardless of the choice of bg ROI. Significant differences (P <0.01) between bg ROIs were only observed in the 120-180s time interval between the C-shape and cranial + caudal bg ROI, and between the caudolateral and cranial + caudal bg ROI. The caudolateral bg ROI in the 60-180 s time interval showed the highest correlation coefficient (r = 0.882) between (99m)Tc-DTPA and (51)Cr-EDTA, although a significant difference (P <0.05) was present between both techniques.

"Apraxic dysgraphia" in a 15-year-old left-handed patient: disruption of the cerebello-cerebral network involved in the planning and execution of graphomotor movements.

Apraxic agraphia is a peripheral writing disorder caused by neurological damage. It induces a lack or loss of access to the motor engrams that plan and programme the graphomotor movements necessary to produce written output. The neural network subserving handwriting includes the superior parietal region, the dorsolateral and medial premotor cortex and the thalamus of the dominant hemisphere. Recent studies indicate that the cerebellum may be involved as well. To the best of our knowledge, apraxic agraphia has not been described on a developmental basis. This paper reports the clinical, neurocognitive and (functional) neuroimaging findings of a 15-year-old left-handed patient with an isolated, non-progressive developmental handwriting disorder consistent with a diagnosis of "apraxic dysgraphia". Gross motor coordination problems were objectified as well but no signs of cerebellar, sensorimotor or extrapyramidal dysfunction of the writing limb were found to explain the apraxic phenomena. Brain MRI revealed no supra- and infratentorial damage but quantified Tc-99m-ECD SPECT disclosed decreased perfusion in the anatomoclinically suspected prefrontal and cerebellar brain regions crucially involved in the planning and execution of skilled motor actions. This pattern of functional depression seems to support the hypothesis that "apraxic dysgraphia" might reflect incomplete maturation of the cerebello-cerebral network involved in handwriting. In addition, it is hypothesized that "apraxic dysgraphia" may have to be considered to represent a distinct nosological category within the group of the developmental dyspraxias following dysfunction of the cerebello-cerebral network involved in planned actions.

Regional brain perfusion in 12 cats measured with technetium-99m-ethyl cysteinate dimer pinhole single photon emission computed tomography (SPECT).

With the use of perfusion tracers, in vivo examination of the regional cerebral blood flow in cats can be performed with single photon emission computed tomography (SPECT). Reliable perfusion data of normal, healthy cats are necessary for future clinical studies or other research use. Therefore, this dataset of the regional perfusion pattern of the normal feline brain was created. Twelve cats were used in this study. Technetium-99m-ethyl cysteinate dimer ((99m)Tc-ECD) was injected intravenously and the acquisition, using a triple head gamma camera equipped with three multi-pinhole collimators (pinhole SPECT), was started 40 mins after tracer administration under general anaesthesia. Nineteen regions of interest were defined using 7T magnetic resonance images of the feline brain and a topographical atlas. Regional counts were normalised to the counts of two reference regions: the total brain and the cerebellum. The highest tracer uptake was noticed in the subcortical structures, and the lowest in the frontal cortex and the cerebellum. Also left-right asymmetry in the temporal cortex and a rostrocaudal gradient of 5% were observed.

Standardized added metabolic activity (SAM): a partial volume independent marker of total lesion glycolysis in liver metastases.

PURPOSE: The standardized added metabolic activity (SAM) is a new marker of total lesion glycolysis that avoids partial volume effect (PVE) and thresholding. SAM is calculated by drawing a volume of interest (VOI(1)) around the tumour and a larger VOI (VOI(2)) around VOI(1). Subtracting the background activity in VOI(2)-VOI(1) from VOI(1) yields SAM. If VOI(1) is set at a reasonable distance from the tumour, PVE are avoided. Phantom and initial clinical validation data are presented. METHODS: Spheres of a Jaszczak phantom were filled with a 5.4, 3.64 and 2.0 times higher concentration relative to background activity and positron emission tomography (PET) data were acquired during 10 min. SAM of all spheres was expressed as a percentage of the expected value (the actual activity ratio minus 1). In 15 patients a 10-min list-mode acquisition PET study centred on their primary squamous cell carcinoma (PSCC) was performed and images of 1-10 min reconstructed. SAM1-9min values of PSCC were expressed as a percentage of SAM10min. Nineteen patients suffering from liver metastases treated with chemotherapy underwent PET/CT prior to (scan 1) and after 3-6 cycles of chemotherapy (scan 2). SAM and maximum standardized uptake values (SUV(max)) of the liver lesions on scan 1 (SAM1 and SUV(max)1) and the percentage reduction between both ΔSAM and ΔSUV(max) were related to Response Evaluation Criteria in Solid Tumors (RECIST) response. RESULTS: For the phantom acquisitions, the mean normalized SAM/sphere volume calculated was 94.9 % (SD 5.9 %) of the expected value. In the PSCC patients, the mean difference between SAM1min and SAM10min was only 4 % (SD 5 %). SUV(max)1min and SUV(max)10min proved to be not significantly different, but the variability was slightly larger than that of SAM (SD 6.4 %). SAM1 and ΔSAM values for responders versus non-responders were, respectively, 57 (SD 119) versus 297 (SD 625) for SAM1 (p = 0.2) and 99 % (SD 3 %) versus 32 % (SD 44 %) for ΔSAM (p = 0.001). SUV(max)1 and ΔSUV(max) values in responders versus non-responders were, respectively, 3.9 (SD 2.4) versus 6.3 (SD 3.1) for SUV(max)1 (p = 0.08) and 94 % (SD 17) versus 7 % (SD 40 %) for ΔSUV(max) (p = 0.0001). The AUC of ΔSAM and ΔSUV(max) were not significantly different on receiver-operating characteristic (ROC) analysis (AUC 1.0 and 0.99, respectively, p = 0.6). CONCLUSION: SAM is a promising parameter for tumour response assessment of liver metastases by means of (18)F-fluorodeoxyglucose PET.