Quantification of brain cholinergic denervation in Alzheimer's disease using PET imaging with [18F]-FEOBV.

18F-fluoroethoxybenzovesamicol (FEOBV) is a new PET radiotracer that binds to the vesicular acetylcholine transporter. In both animals and healthy humans, FEOBV was found sensitive and reliable to characterize presynaptic cholinergic nerve terminals in the brain. It has been used here for we believe the first time in patients with Alzheimer's disease (AD) to quantify brain cholinergic losses. The sample included 12 participants evenly divided in healthy subjects and patients with AD, all assessed with the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) cognitive scales. Every participant underwent three consecutive PET imaging sessions with (1) the FEOBV as a tracer of the cholinergic terminals, (2) the 18F-NAV4694 (NAV) as an amyloid-beta tracer, and (3) the 18F-Fluorodeoxyglucose (FDG) as a brain metabolism agent. Standardized uptake value ratios (SUVRs) were computed for each tracer, and compared between the two groups using voxel wise t-tests. Correlations were also computed between each tracer and the cognitive scales, as well as between FEOBV and the two other radiotracers. Results showed major reductions of FEOBV uptake in multiple cortical areas that were evident in each AD subject, and in the AD group as a whole when compared to the control group. FDG and NAV were also able to distinguish the two groups, but with lower sensitivity than FEOBV. FEOBV uptake values were positively correlated with FDG in numerous cortical areas, and negatively correlated with NAV in some restricted areas. The MMSE and MoCA cognitive scales were found to correlate significantly with FEOBV and with FDG, but not with NAV. We concluded that PET imaging with FEOBV is more sensitive than either FDG or NAV to distinguish AD patients from control subjects, and may be useful to quantify disease severity. FEOBV can be used to assess cholinergic degeneration in human, and may represent an excellent biomarker for AD.

Amyloid-ß and hyperphosphorylated tau synergy drives metabolic decline in preclinical Alzheimer's disease.

This study was designed to test the interaction between amyloid-ß and tau proteins as a determinant of metabolic decline in preclinical Alzheimer's disease (AD). We assessed 120 cognitively normal individuals with [18F]florbetapir positron emission tomography (PET) and cerebrospinal fluid (CSF) measurements at baseline, as well as [18F]fluorodeoxyglucose ([18F]FDG) PET at baseline and at 24 months. A voxel-based interaction model was built to test the associations between continuous measurements of CSF biomarkers, [18F]florbetapir and [18F]FDG standardized uptake value ratios (SUVR). We found that the synergistic interaction between [18F]florbetapir SUVR and CSF phosphorylated tau (p-tau) measurements, rather than the sum of their independent effects, was associated with a 24-month metabolic decline in basal and mesial temporal, orbitofrontal, and anterior and posterior cingulate cortices (P<0.001). In contrast, interactions using CSF amyloid-ß1-42 and total tau biomarkers did not associate with metabolic decline over a time frame of 24 months. The interaction found in this study further support the framework that amyloid-ß and hyperphosphorylated tau aggregates synergistically interact to cause downstream AD neurodegeneration. In fact, the regions displaying the metabolic decline reported here were confined to brain networks affected early by amyloid-ß plaques and neurofibrillary tangles. Preventive clinical trials may benefit from using a combination of amyloid-ß PET and p-tau biomarkers to enrich study populations of cognitively normal subjects with a high probability of disease progression in studies, using [18F]FDG as a biomarker of efficacy.

Dopamine cross-sensitization between psychostimulant drugs and stress in healthy male volunteers.

Dysregulation of the stress response system is a potential etiological factor in the development of and relapse to multiple neuropsychiatric disorders. Previously we reported that repeated intermittent d-amphetamine administration can lead to progressively greater dopamine release, thereby providing evidence of drug-induced neurochemical sensitization. Here, we test the hypothesis that repeated exposure to d-amphetamine increases dopaminergic responses to stress; that is, produces cross-sensitization. Using positron emission tomography, we measured in 17 healthy male volunteers (mean ± s.d. = 22.1 ± 3.4 years) [(11)C]raclopride binding responses to a validated psychosocial stress task before and 2 weeks after a regimen of repeated d-amphetamine (3 × 0.3 mg kg(-1), by mouth; n = 8) or placebo (3 × lactose, by mouth; n = 9). Mood and physiological measurements were recorded throughout each session. Before the d-amphetamine regimen, exposure to the stress task increased behavioral and physiological indices of stress (anxiety, heart rate, cortisol, all P ⩽ 0.05). Following the d-amphetamine regimen, the stress-induced cortisol responses were augmented (P < 0.04), and voxel-based analyses showed larger stress-induced decreases in [(11)C]raclopride non-displaceable binding potential across the striatum. In the placebo group, re-exposure to stress led to smaller clusters of decreased [(11)C]raclopride binding, primarily in the sensorimotor striatum (P < 0.05). Together, this study provides evidence for drug × stress cross-sensitization; moreover, random exposure to stimulants and/or stress cumulatively, while enhancing dopamine release in striatal areas, may contribute to a lowered set point for psychopathologies in which altered dopamine neurotransmission is invoked.

Validation of the transporter ligand cyanoimipramine as a marker of serotonin innervation density in brain.

UNLABELLED: Radiolabeled ligands of monoamine transporters have already been used to visualize cerebral monoamine innervation by tissue autoradiography and by PET or SPECT in vivo. METHODS: A sampling technique was developed to allow for both the autoradiographic counting of serotonin (5-HT) axonal varicosities, labeled by uptake and storage of [3H]5-HT, and the measurement of the binding of [3H]cyanoimipramine ([3H]CYI), a specific 5-HT transporter ligand, in adjacent slices of adult rat neostriatum. The experiments were conducted in normal, decreased (after 5,7-dihydroxytryptamine lesions in adults) or increased (after 6-hydroxydopamine lesions in neonates) states of neostriatal 5-HT innervation. RESULTS: In normal tissue, the regional density of [3H]CYI binding faithfully reproduced rostrocaudal variations in the number of [3H]5-HT-labeled axonal varicosities. Pairs of values from all three experimental groups showed a highly significant linear correlation (r = 0.93) between the density of [3H]CYI binding and the number of 5-HT varicosities per cubic millimeter of tissue. The intercept of the regression line was close to zero; this confirmed the selectivity of the ligand. CONCLUSION: Under drug-free conditions, specific [3H]CYI binding is a good quantitative index of 5-HT innervation density in brain tissue and is not significantly up- or downregulated on 5-HT denervation or hyperinnervation. When it is adequately labeled, such a ligand might therefore be appropriate to quantify regional 5-HT innervation in vivo by PET or SPECT. The present approach should also be useful to select ligands to quantify 5-HT and monoamine systems.

Evaluation of vasospasm secondary to subarachnoid hemorrhage with technetium-99m-hexamethyl-propyleneamine oxime (HM-PAO) tomoscintigraphy.

Vasospasm of intracranial vessels is difficult to diagnose on clinical ground alone. Still, a clear diagnosis is important because it can impact on surgical timing; and also because it can help evaluate new treatments. Fifteen patients with sub-arachnoid hemorrhage secondary to aneurysm rupture were submitted to a total of 26 tomographic technetium-99m-hexamethyl-propyleneamine oxime (99mTc-HM-PAO) brain examinations that were correlated with temporally close (generally less than 24 hr) angiography or transmission computed tomography (TCT). Nine of 10 angiographically confirmed episodes of spasm and 6 of 6 infarcts seen on angiography or TCT were correctly diagnosed with 99mTc-HM-PAO. One normal scintigraphic exam was angiographically doubtful, one positive 99mTc-HM-PAO study was normal on angiography (sub-radiologic spasm?), one technically poor scintigraphy was positive for spasm on angiograms, and eight exams were normal for spasm with all modalities. We had agreement between tests in 23 of 26 series of exams (88%) obtained in 15 patients. We think that 99mTc-HM-PAO tomography should be useful for the evaluation of patients with suspected vasospasm.

Quantification of the serotonin hyperinnervation in adult rat neostriatum after neonatal 6-hydroxydopamine lesion of nigral dopamine neurons.

Light microscope autoradiography after uptake and storage of tritiated serotonin (5-HT) in brain slices was used to count 5-HT axon terminals (varicosities) in the 5-HT-hyperinnervated neostriatum of adult rats subjected to neonatal 6-hydroxydopamine treatment and age-matched, normal controls. After correction for incomplete autoradiographic exposure and for section thickness, the results were expressed in millions of varicosities per mm3 of tissue. Control values ranged from 4.8 in the rostral to 6.3 in the caudal neostriatum (5.8 at intermediate level), for an average of 5.6. The corresponding values in 5-HT-hyperinnervated tissue ranged from 9.7 to 7.7 (8.8 at intermediate level), for an average of 8.7 and increases of 102%, 52% and 22% above control in the rostral, intermediate and caudal neostriatum, respectively (average increase of 55%). These data confirmed the predilection of the 5-HT hyperinnervation for the rostral neostriatum and demonstrated its presence in the caudal neostriatum also.

Absence of correlation between amobarbital distribution as assessed with SPECT brain perfusion imaging and behavioral manifestations during the intracarotid amobarbital procedure (Wada test).

1. The IAP is used presurgically in patients with temporal lobe epilepsy to predict the effects on LTM and language of the planned temporal lobectomy. This prognosis presumes that a similar pattern of perfusion will result in anesthesia of the same cerebral regions in most patients. 2. Coinjection of Tc-99m HMPAO with the barbiturate during the IAP has been used to ascertain whether this actually is true, with variable results. Moreover, most studies document only unilateral IAPs and do not report on behavioral performance. 3. The authors coinjected Tc-99m HMPAO and amobarbital in 33 IAPs from 18 patients (15 injected bilaterally, 3 unilaterally) to clarify this and to evaluate the relationship of the perfusion pattern to behavioral performance; SPECT results were also compared to angiographic evaluation obtained at the time of catheter placement. 4. SPECT perfusion data was rated for presence/absence and intensity of perfusion to the ACA, MCA, PCA territories and to H, i or c to the injection site. V, STM and LTM were graded according to a standardized protocol. 5. MCAi was perfused in 100% of cases, ACAi in 91%, PCAi in 21% and Hi in only 6%. Cross-over flow was shown in 9 studies; 50% of the patients in whom both sides were injected (on different days) had crossover, involving the ACAc territory in 80% of cases. As expected, injection on the non-ES was associated with a significantly worse LTM performance than on the ES (p = 0.006). There was no relationship between the perfusion pattern and the V level of the patients (a potential confounding variable in memory/language evaluation) during IAP, nor between perfusion pattern and LTM. STM was significantly adversely affected by the presence of crossover perfusion. Angiography in general overestimated the extent of cerebral perfusion demonstrated by SPECT, most probably because of the markedly different injection conditions. 6. Despite the best efforts to standardize injections, the perfusion pattern has been mostly unpredictable in the patients. Moreover, it has little bearing on their behavioral performance, except for the prediction of poor STM performance (the clinical implications of this remaining dubious). Marked LTM alterations after non-ES injections confirm remote hippocampal effects in the presence of only rare direct perfusion of that region. Tc-99m HMPAO/Amobarbital coinjection was unhelpful from a clinical perspective, most probably because a large part of the effects of amobarbital arise from deafferentation of regions not directly perfused by the anesthetic agent.

Striatal D2 receptor binding in sleep bruxism: a controlled study with iodine-123-iodobenzamide and single-photon-emission computed tomography.

The neurochemical mechanisms underlying sleep bruxism are little understood at present. However, recent pharmacologic evidence suggests that the central dopaminergic system may be involved in the pathophysiology of sleep bruxism. This possibility was further assessed by means of functional neuroimaging of dopamine D2 receptors with single-photon-emission computed tomography (SPECT). Ten controls and ten patients with polysomnographically confirmed sleep bruxism were injected intravenously with 185 MBq (5 mCi) iodine-123-iodobenzamide, a specific D2 receptor antagonist radioligand, and data acquisition was performed 90 min post-injection. Following image reconstruction, it was found that striatal D2 receptor binding potential (basal ganglia/background ratio) did not differ significantly between bruxism patients and controls. However, side-to-side differences between unilateral values of the striatal D2 binding potential ("highest side" values minus "lowest side" values) were significantly larger for the bruxism patients (p < 0.001, by two-independent-samples t test with pooled variances). It was concluded that an abnormal side imbalance in striatal D2 receptor expression can be associated with sleep bruxism. This reinforces the possibility that the central dopaminergic system plays a role in the pathophysiology of this disorder.

Effects of the D2 receptor agonist bromocriptine on sleep bruxism: report of two single-patient clinical trials.

An altered dopamine receptor status has been associated with sleep bruxism. Evidence from a functional neuro-imaging study has implicated an abnormal side imbalance in striatal D2 receptor expression in its pathophysiology. To assess the significance of this finding, we studied the effects of short-term administration of the preferential dopamine D2 receptor agonist bromocriptine on sleep bruxism in a double-blind, placebo-controlled polysomnographic and neuro-imaging study with a single crossover design. Six otherwise healthy and drug-free patients with sleep bruxism were entered into the trial. One of the patients dropped out due to an intercurrent illness, while three others were discontinued from the study due to severe adverse reactions to bromocriptine. Because of the high frequency and intensity of the side-effects, the trial was interrupted. Two patients, however, completed the trial without any adverse reactions. Their outcome measures are presented as single-patient clinical trials. Following a two-week administration of bromocriptine, both patients showed a decrease in the number of bruxism episodes per hour of sleep of about 20% to 30% with respect to the placebo. WHile no significant differences between both conditions (i.e., placebo and bromocriptine) were found for the number of bruxism bursts per episode, significantly lower root-mean-squared EMG levels per bruxism burst occurred during bromocriptine use. In association with this polysomnographically established attenuation of sleep bruxism, bromocriptine afforded a decreased normal side distribution of striatal D2 receptor binding, as was evidenced by single-photon-emission computed tomography using the radioactive D2 receptor antagonist iodine-123-iodobenzamide. This study supports previous suggestions that the central dopaminergic system may be involved in the modulation of sleep bruxism. To see if the present findings apply across a population, investigators should use a peripheral D-2 antagonist to prevent side-effects.

Double-blind, crossover, placebo-controlled trial of bromocriptine in patients with sleep bruxism.

This study was designed to assess the effects of bromocriptine, a dopamine D2 receptor agonist, on sleep bruxism. Seven otherwise healthy patients with severe and frequent sleep bruxism participated in this randomized, double-blind, placebo-controlled study. The study used a crossover design that included 2 weeks of active treatment or placebo with a washout period of 1 week. To further evaluate whether bromocriptine influences striatal D2 receptor binding, we used iodine-123-iodobenzamide single photon emission computed tomography (SPECT) under both placebo and bromocriptine regimens. Bromocriptine did not reduce the frequency of episodes of bruxism during sleep (mean +/- SEM, 9.0 +/- 1.0 and 9.6 +/- 1.5 bruxism episodes per hour for placebo and bromocriptine, respectively) or the amplitude of masseter muscle contractions (root mean square values, 48.2 +/- 15.5 microV and 46.9 +/- 12.7 microV for placebo and bromocriptine, respectively). SPECT also failed to reveal that either treatment had any influence on striatal D2 binding (values for total binding in counts/pixel, 1.80 [1.72-1.93] and 1.79 [1.56-1.87] for placebo and bromocriptine, respectively). This study shows that a nightly dose of bromocriptine does not exacerbate or reduce sleep bruxism motor activity.

Dipyridamole testing compared to exercise stress for thallium-201 imaging in patients with left bundle branch block.

Because of numerous reports of false positive results with thallium-201 (Tl-201) stress testing in patients with left bundle branch block, the authors decided to evaluate another mode of coronary vasodilatation, dipyridamole, for the diagnosis of coronary atheromatosis. Nine patients were prospectively studied with stress and dipyridamole Tl-201 scintigraphy; both tests were performed within three to 79 days of one another. Five of the patients also had coronary angiograms (four within one year, one five years earlier). Four of the patients had normal results with both tests (two normal angiograms, two not performed); two had reversible septal defects with stress-induced coronary vasodilatation but normal dipyridamole studies (only one had an angiogram, which was normal); one patient had a fully reversible septal defect with stress and a fixed defect with dipyridamole (normal angiogram); one had a partially reversible septal stress defect which was fixed with dipyridamole; and one had a normal stress study but a reversible septal defect with dipyridamole (an angiogram performed five years earlier showed 30 to 40% stenosis of the anterior descending artery). Because it seems that dipyridamole produces fewer false positive results, it should be used instead of stress testing to induce coronary vasodilatation in patients with left bundle branch block.

Lack of associations between occlusal and cephalometric measures, side imbalance in striatal D2 receptor binding, and sleep-related oromotor activities.

AIMS: First, to evaluate possible orofacial morphologic differences between sleep bruxers and non-bruxers, and second, to determine possible correlations between morphologic factors and striatal D2 receptor expression in persons with sleep-related oromotor activities. METHODS: Twenty subjects were included in this study; half of them had polysomnographically confirmed oromotor values above the cutoff points for sleep bruxism. For all participants, 26 standard occlusal measures were recorded clinically and from dental study casts. In addition, 25 standard angular and linear measures were taken from standardized cephalometric films, and variables were derived to evaluate dental and skeletal relationships. Fourteen of the 20 participants had also participated in a previous study that included iodine-123-iodobenzamide (I-123-IBZM) and single-photon emission-computed tomography (SPECT). For them, the side-to-side difference in striatal D2 receptor binding was determined as the neurochemical outcome measure. RESULTS: Following the classical Bonferroni adjustment for multiple testing, no morphologic differences were found between the sleep bruxers and the non-bruxers. In addition, none of the morphologic variables were significantly associated with the neuroimaging data. CONCLUSION: Taking into account the low power of this retrospective, exploratory study, the results suggest that the orofacial morphology of sleep bruxers does not differ from that of non-bruxers. In addition, morphologic factors are probably not involved in the asymmetry in striatal D2 receptor distribution that was previously observed in association with sleep bruxism.

Lymphoscintigraphic demonstration of intestinal lymphangiectasia.

The authors report a case of intestinal lymphangiectasia that was clearly demonstrated during abdominal lymphoscintigraphy using Tc-99m Sb colloid. Although lymphoscintigraphy has been used in many different clinical situations, this is, to our knowledge, the first scintigraphic description of this disease. Clinical and pathologic presentations of intestinal lymphangiectasia are briefly reviewed. Some possible approaches to the confirmation of the presence of a protein-losing gastroenteropathy are mentioned.

Technetium-99m HMPAO imaging in Sturge-Weber syndrome.

The Tc-99m HMPAO brain imaging confirmed marked hypoperfusion secondary to anomalous cerebral venous drainage of the Sturge-Weber syndrome. Until now, this had been a hypothesis suggested by results obtained from conventional brain scans and cerebral arteriography.

[The role of echography in splenic injuries in children]. / Le rôle de l'échographie dans le traumatisme splénique chez l'enfant.

We have reviewed 39 cases of ruptured spleen in children from 1979 to march 1983 at Ste-Justine Hospital in Montreal. We were mainly interested in the role of ultrasonography, its value and limitations. The practical management is exposed. To the best of our knowledge, it is the first report of this kind in pediatrics.

Motion compensation for fully 4D PET reconstruction using PET superset data.

Fully 4D PET image reconstruction is receiving increasing research interest due to its ability to significantly reduce spatiotemporal noise in dynamic PET imaging. However, thus far in the literature, the important issue of correcting for subject head motion has not been considered. Specifically, as a direct consequence of using temporally extensive basis functions, a single instance of movement propagates to impair the reconstruction of multiple time frames, even if no further movement occurs in those frames. Existing 3D motion compensation strategies have not yet been adapted to 4D reconstruction, and as such the benefits of 4D algorithms have not yet been reaped in a clinical setting where head movement undoubtedly occurs. This work addresses this need, developing a motion compensation method suitable for fully 4D reconstruction methods which exploits an optical tracking system to measure the head motion along with PET superset data to store the motion compensated data. List-mode events are histogrammed as PET superset data according to the measured motion, and a specially devised normalization scheme for motion compensated reconstruction from the superset data is required. This work proceeds to propose the corresponding time-dependent normalization modifications which are required for a major class of fully 4D image reconstruction algorithms (those which use linear combinations of temporal basis functions). Using realistically simulated as well as real high-resolution PET data from the HRRT, we demonstrate both the detrimental impact of subject head motion in fully 4D PET reconstruction and the efficacy of our proposed modifications to 4D algorithms. Benefits are shown both for the individual PET image frames as well as for parametric images of tracer uptake and volume of distribution for (18)F-FDG obtained from Patlak analysis.