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.

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.

Image restoration using functional and anatomical information fusion with application to SPECT-MRI images.

Image restoration is usually viewed as an ill-posed problem in image processing, since there is no unique solution associated with it. The quality of restored image closely depends on the constraints imposed of the characteristics of the solution. In this paper, we propose an original extension of the NAS-RIF restoration technique by using information fusion as prior information with application in SPECT medical imaging. That extension allows the restoration process to be constrained by efficiently incorporating, within the NAS-RIF method, a regularization term which stabilizes the inverse solution. Our restoration method is constrained by anatomical information extracted from a high resolution anatomical procedure such as magnetic resonance imaging (MRI). This structural anatomy-based regularization term uses the result of an unsupervised Markovian segmentation obtained after a preliminary registration step between the MRI and SPECT data volumes from each patient. This method was successfully tested on 30 pairs of brain MRI and SPECT acquisitions from different subjects and on Hoffman and Jaszczak SPECT phantoms. The experiments demonstrated that the method performs better, in terms of signal-to-noise ratio, than a classical supervised restoration approach using a Metz filter.

Acute prefrontal cortex TMS in healthy volunteers: effects on brain 11C-alphaMtrp trapping.

High-frequency repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral prefrontal cortex (LDLPFC) is a technique with purported efficacy as a treatment for major depression. Here, we assessed in vivo, in healthy volunteers, the effect of acute rTMS of the LDLPFC, relative to the stimulation of the left occipital cortex (LOC), on brain regional serotonin synthesis capacity, using the [(11)C]-alpha-methyl-tryptophan ((11)C-alphaMtrp)/PET method. Ten subjects were studied twice, once following rTMS of the LDLPFC and once following rTMS of the LOC in a randomized counterbalanced order. Three blocks of 15 trains of 10 Hz rTMS were delivered 10 min apart. Behavioural and autonomic measures were recorded before and after each rTMS session. Comparisons of TMS-related changes in regional normalized brain uptake and trapping of (11)C-alphaMtrp (K*) values were carried out using SPM99. Statistically significant regional differences were identified on the basis of an extent threshold of 50 voxels, with a peak threshold of p=0.005 uncorrected. Behavioural and autonomic measures were unaffected by rTMS. Relative to LOC stimulation, LDLPFC rTMS was associated with marked changes in normalized K* in limbic areas, with significantly lower values in the left parahippocampal gyrus (BA 28) and the right insula (BA 13), and higher values in the right cingulate gyrus (BA 31) and cuneus (BA 18). These findings indicate that acute rTMS of the LDLPFC in healthy volunteers modulates aspects of tryptophan/5-HT metabolism in limbic areas. Such adaptive changes may contribute to the mechanism of action of prefrontal rTMS in major depression.

Assessing whole brain perfusion changes in patients with REM sleep behavior disorder.

OBJECTIVE: To investigate the regional cerebral perfusion in patients with idiopathic REM behavior disorder (RBD) in order to establish the topography of networks involved. METHODS: We performed cerebral blood flow evaluation using (99m)Tc-Ethylene Cysteinate Dimer (ECD) SPECT on eight patients with polysomnographically confirmed RBD and nine age-matched controls. Comparisons were made using SPM2. RESULTS: We found increased perfusion in the pons and putamen bilaterally and in the right hippocampus. In addition, we observed a decreased perfusion in frontal (Brodmann area [BA] 4, 6, 10, 43, 44, 47 bilaterally and left BA 9, 46) and temporo-parietal (BA 13, 22, 43 bilaterally and left BA 7, 19, 20, 21, 39, 40, 41, 42) cortices. CONCLUSION: Perfusional abnormalities in patients with REM behavior disorder were located in the brainstem, striatum, and cortex. These abnormalities are consistent with the anatomic metabolic profile of Parkinson disease.

A 3D Adaptive Wiener Filter for Restoration of SPECT Images Using MRI as Reference Images.

Single Photon Emission Computed Tomography (SPECT) images suffer from poor resolution and low contrast, which make it difficult for physicians to put an accurate interpretation for diagnosis, in particular, early diagnosis. Although the Wiener filter is a simple and powerful tool to restore degraded images, the requirement for a priori information limits its application. In this paper, we present a new 3D adaptive Wiener filter for restoration of brain SPECT images with a priori data taken from a magnetic resonance imaging (MRI) of the same patient. The proposed algorithm automatically and significantly improve the contrast and sharpness of synthetic and real SPECT images while keeping amplification of noise under acceptable level.

Comparison between olanzapine and haloperidol on procedural learning and the relationship with striatal D2 receptor occupancy in schizophrenia.

The striatum is known to play a primary role in procedural learning. In this study, the authors simultaneously assessed the effects of two antipsychotic drugs on procedural learning and on striatal dopamine (D2) receptor occupancy. Twenty-seven patients receiving either olanzapine or haloperidol as antipsychotic medication were assessed with the Computed Visual Tracking Task (CVTT) and Single Photon Emission Computed Tomography (SPECT) following the administration of Iodine 123-IBZM (123I-IBZM), a radioligand with a high affinity and specificity for the D2 receptors. The results showed poorer procedural learning in the haloperidol-treated patients than in normal control subjects, while no difference could be found between olanzapine-treated patients and normal control subjects. In the haloperidol but not the olanzapine group, significant correlations were found between procedural learning deficits and striatal D2 receptor occupancy. However, there was no significant difference in D2 receptor occupancy between olanzapine- and haloperidol-treated patients, and this may be related to the high doses of olanzapine and low doses of haloperidol administered. The authors concluded that: 1) striatal D2 receptor blockade may alter procedural learning in humans; and 2) olanzapine may have a protective effect on procedural learning, even at doses that produce striatal D2 receptor occupancy as high as that found with haloperidol. This protective effect of olanzapine may be related to its atypical pharmacological properties.

Alpha-[11C] methyl-L-tryptophan and glucose metabolism in patients with temporal lobe epilepsy.

OBJECTIVE: To determine whether metabolism in the brain serotonergic system, including the kynurenine pathway, is involved in temporal lobe epilepsy (TLE). METHODS: The authors studied 14 patients with intractable TLE by PET using alpha-[11C] methyl-L-tryptophan (alpha-MTrp) and 2-[18F]-fluoro-deoxy-glucose (FDG) and compared results with 21 healthy control subjects who had alpha-MTrp PET studies. Seven patients had unilateral hippocampal atrophy (HA), and seven had normal hippocampal volumes (NV). The regional uptake constant (K*) for alpha-MTrp and regional FDG uptake were calculated in regions with high serotonergic innervation, including the hippocampus, amygdala, lateral temporal lobe, frontal lobe, thalamus, lenticular nucleus, and cingulate cortex. RESULTS: A significant increase of alpha-MTrp uptake was observed in the hippocampus ipsilateral to the seizure focus in seven TLE patients with NV compared to seven patients with HA as well as to healthy controls. In patients with TLE, glucose utilization in the lateral temporal lobe ipsilateral to the seizure focus was correlated negatively with K* for alpha-MTrp in the ipsilateral hippocampus and positively with K* in the ipsilateral lenticular nucleus and cingulate cortex. Glucose utilization in the frontal lobe ipsilateral to the seizure shows a reduction in the glucose utilization which relates to the increase in the alpha-MTrp uptake in the ipsilateral lateral temporal lobe. CONCLUSION: This study demonstrates dysfunction of the serotonergic system, which could include metabolism through the kynurenine pathway in TLE patients with normal hippocampal volumes. alpha-MTrp PET studies might be useful for lateralizing the epileptic focus in TLE patients with normal hippocampal volumes.

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.

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.

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.

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.

Comparative evaluation of [3H]WIN 35428 and [3H]GBR 12935 as markers of dopamine innervation density in brain.

WIN 35428 and GBR 12935, two uptake blocker ligands of the membrane transporter for dopamine (DA), were evaluated as quantitative markers of DA innervation density in CNS tissue. From alternate rat brain slices respectively processed for either light microscope or film autoradiography, counts of DA axon terminals (varicosities) labeled by uptake/storage of [3H]DA were matched with densitometric measurements of the specific binding of [3H]WIN 35428 and [3H]GBR 12935 in the same anatomical areas. The relation between the two parameters was examined in 1) the normal cingulate cortex; 2) the neostriatum severely DA-denervated by unilateral intramesencephalic injections of 6-hydroxydopamine; and 3) the neostriatum, partly DA-reinnervated by an intrastriatal graft of fetal mesencephalic neurons after prior 6-hydroxydopamine lesion. For technical reasons, the hyperdense DA innervation of normal striatum was not amenable to such correlative testing. Data were subjected to multilevel analysis. Specific [3H]WIN binding at 37 degrees C was tightly and linearly correlated with the number of DA varicosities over the full range of DA innervation densities tested. The regression lines for intact cortex and for DA-denervated as well as DA-reinnervated neostriatum had the same slope and crossed the ordinate near zero. In contrast, [3H]GBR 12935 binding at 37 degrees C showed no correlation with the number of DA varicosities. A linear correlation could be obtained after incubation with [3H]GBR 12935 at 4 degrees C in the presence of ZnSO4, but the intercept of this regression line remained significantly above zero at origin, indicating extraneous binding to non-DA transporter sites. Providing that the hyperdense DA innervation of the normal neostriatum does not generate a particular problem in vivo as it does in vitro. WIN 35428, but not GBR 12935, might satisfy the selectivity and sensitivity requirements of a quantitative marker of DA innervation density for eventual use in positron emission tomographic studies.

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.

Autosplenectomy in systemic lupus erythematosus.

Autosplenectomy in systemic lupus erythematosus (SLE) is associated with a high mortality rate due to Streptococcus pneumoniae sepsis. We describe 2 patients who developed autosplenectomy in the setting of an acute SLE exacerbation. Followup of both patients 12 and 5.5 years after the initial diagnosis of autosplenectomy revealed persistent absence of the spleen. Pneumococcal vaccine was given to both patients. In contrast with reports describing life threatening infections in 46.7% of asplenic patients with SLE, none developed during prolonged followup of our patients. Our data and review of 13 other patients with SLE with autosplenectomy suggest that the 23-valent pneumococcal vaccine should be given promptly to patients with SLE when a diagnosis of autosplenectomy is established.