Simultaneous quantitative susceptibility mapping and Flutemetamol-PET suggests local correlation of iron and ß-amyloid as an indicator of cognitive performance at high age.

The accumulation of ß-amyloid plaques is a hallmark of Alzheimer's disease (AD), and recently published data suggest that increased brain iron burden may reflect pathologies that synergistically contribute to the development of cognitive dysfunction. While preclinical disease stages are considered most promising for therapeutic intervention, the link between emerging AD-pathology and earliest clinical symptoms remains largely unclear. In the current study we therefore investigated local correlations between iron and ß-amyloid plaques, and their possible association with cognitive performance in healthy older adults. 116 older adults (mean age 75 ±â€¯7.4 years) received neuropsychological testing to calculate a composite cognitive score of performance in episodic memory, executive functioning, attention, language and communication. All participants were scanned on a combined PET-MRI instrument and were administered T1-sequences for anatomical mapping, quantitative susceptibility mapping (QSM) for assessing iron, and 18F-Flutemetamol-PET for estimating ß-amyloid plaque load. Biological parametric mapping (BPM) was used to generate masks indicating voxels with significant (p < 0.05) correlation between susceptibility and 18F-Flutemetamol-SUVR. We found a bilateral pattern of clusters characterized by a statistical relationship between magnetic susceptibility and 18F-Flutemetamol-SUVR, indicating local correlations between iron and ß-amyloid plaque deposition. For two bilateral clusters, located in the frontal and temporal cortex, significant relationships (p<0.05) between local ß-amyloid and the composite cognitive performance score could be observed. No relationship between whole-cortex ß-amyloid plaque load and cognitive performance was observable. Our data suggest that the local correlation of ß-amyloid plaque load and iron deposition may provide relevant information regarding cognitive performance of healthy older adults. Further studies are needed to clarify pathological correlates of the local interaction of ß-amyloid, iron and other causes of altered magnetic susceptibility.

Colocalization of cerebral iron with Amyloid beta in Mild Cognitive Impairment.

Quantitative Susceptibility Mapping (QSM) MRI at 7 Tesla and 11-Carbon Pittsburgh-Compound-B PET were used for investigating the relationship between brain iron and Amyloid beta (Aß) plaque-load in a context of increased risk for Alzheimer's disease (AD), as reflected by the Apolipoprotein E ε4 (APOE-e4) allele and mild cognitive impairment (MCI) in elderly subjects. Carriers of APOE-e4 with normal cognition had higher cortical Aß-plaque-load than non-carriers. In MCI an association between APOE-e4 and higher Aß-plaque-load was observable both for cortical and subcortical brain-regions. APOE-e4 and MCI was also associated with higher cortical iron. Moreover, cerebral iron significantly affected functional coupling, and was furthermore associated with increased Aß-plaque-load (R2-adjusted = 0.80, p < 0.001) and APOE-e4 carrier status (p < 0.001) in MCI. This study confirms earlier reports on an association between increased brain iron-burden and risk for neurocognitive dysfunction due to AD, and indicates that disease-progression is conferred by spatial colocalization of brain iron deposits with Aß-plaques.

Smoking but not cocaine use is associated with lower cerebral metabotropic glutamate receptor 5 density in humans.

Long-lasting neuroadaptations in the glutamatergic corticostriatal circuitry have been suggested to be responsible for the persisting nature of drug addiction. In particular, animal models have linked the metabotropic glutamate receptor 5 (mGluR5) to drug-seeking behavior and extinction learning. Accordingly, blocking mGluR5s attenuated self-administration of cocaine and other addictive drugs in rats. How these animal findings extend to humans remains unclear. Therefore, we investigated if human cocaine users (CU) exhibit altered mGluR5 availability compared with drug-naïve control subjects. Seventeen male controls (11 smokers) and 18 male cocaine users (13 smokers) underwent positron emission tomography with (11)C-ABP688 to quantify mGluR5 availability in 12 volumes of interest in addiction-related brain areas. Drug use was assessed by self-report and quantitative hair toxicology. CU and controls did not significantly differ in regional mGluR5 availability. In contrast, smokers (n=24) showed significantly lower mGluR5 density throughout the brain (mean 20%) compared with non-smokers (n=11). In terms of effect sizes, lower mGluR5 availability was most pronounced in the caudate nucleus (d=1.50, 21%), insula (d=1.47, 20%), and putamen (d=1.46, 18%). Duration of smoking abstinence was positively associated with mGluR5 density in all brain regions of interest, indicating that lower mGluR5 availability was particularly pronounced in individuals who had smoked very recently. Specifically tobacco smoking was associated with lower mGluR5 availability in both CU and controls, while cocaine use was not linked to detectable mGluR5 alterations. These findings have important implications regarding the development of novel pharmacotherapies aimed at facilitating smoking cessation.

Assessment of successful incorporation of cages after cervical or lumbar intercorporal fusion with [(18)F]fluoride positron-emission tomography/computed tomography.

The purpose of this study is to assess the successful incorporation of cages in patients after cervical or lumbar intercorporal fusion with positron-emission tomography/computed tomography (PET/CT). Twenty patients (14 female and 6 male; mean age 58 years, age range 38-73 years) with 30 cervical (n = 13) or lumbar (n = 17) intercorporal fusions were prospectively enrolled in this study. Time interval between last intercorporal intervention and PET/CT ranged from 2 to 116 months (mean 63; median 77 months). IRB approval was obtained for all patients, and written informed consent was obtained from all patients. About 30 min prior to PET/CT scanning, 97-217 MBq (mean 161 MBq) 18F-fluoride were administered intravenously. Patients were imaged in supine position on a combined PET/CT system (Discovery RX/STE, 16/64 slice CT, GE Healthcare). 3D-PET emission data were acquired for 1.5 and 2 min/bed position, respectively, and reconstructed by a fully 3D iterative algorithm (VUE Point HD) using low-dose CT data for attenuation correction. A dedicated diagnostic thin-slice CT was optionally acquired covering the fused region. Areas of increased 18F-fluoride uptake around cages were determined by one double-board certified radiologist/nuclear physician and one board certified radiologist in consensus. In 12/20 (60%) patients, increased 18F-fluoride uptake around cages was observed. Of the 30 intercorporal fusions, 15 (50%) showed increased 18F-fluoride uptake. Median time between intervention and PET/CT examination in cages with increased uptake was 37 months (2-116 months), median time between intervention and PET/CT examination in those cages without increased uptake was 91 months (19-112 months), p (Wilcoxon) = 0.01 (one-sided). 14/29 (48%) cages with a time interval > 1 year between intervention and PET/CT scan showed an increased uptake. In conclusion, PET/CT frequently shows increased 18F-fluoride uptake in cervical and lumbar cages older than 1 year (up to almost 8 years in cervical cages and 10 years in lumbar cages) possibly indicating unsuccessful fusion due to increased stress/microinstability.

First head-to-head comparison of effective radiation dose from low-dose 64-slice CT with prospective ECG-triggering versus invasive coronary angiography.

BACKGROUND: Reduction of radiation burden of multidetector computed tomography coronary angiography (CTCA) has remained an important task. OBJECTIVE: To compare effective radiation dose of low-dose 64-slice CTCA using prospective ECG-triggering versus diagnostic invasive coronary angiography (CA). METHODS: 42 patients referred for elective invasive CA owing to suspected coronary artery disease (CAD) were prospectively enrolled to undergo a low-dose CTCA without calcium scoring within the same day before CA. Dose-area product of diagnostic invasive CA and dose-length product of CTCA were measured, converted into effective radiation dose and compared using Mann-Whitney U tests. In addition, accuracy of CTCA to detect CAD (coronary artery narrowing > or =50%) was assessed using invasive CA as standard of reference. On an intention-to-diagnose basis all non-evaluative vessels were included in the analysis and censored as positive. RESULTS: The estimated mean effective radiation dose was 8.5 (4.4) mSv (range 1.4-20.5 mSv) for diagnostic invasive CA, and 2.1 (0.7) mSv (range 1.0-3.3 mSv) for CTCA (p<0.001). 19 patients (42.9%) had no CAD by invasive CA. 40 (95.2%) patients have been correctly classified as having CAD (23/23) or no CAD (17/19). Over 97% (551/567) of segments were evaluable. Vessel-based analysis revealed sensitivity, specificity, positive and negative predictive value of 94.2% (CI 0.8% to 1.0%), 94.8% (CI 09% to 1.0%), 89.0% (CI 0.8% to 1.0%), 97.4% (CI 09% to 1.0%) and an accuracy of 94.6%. CONCLUSIONS: Low dose CTCA allows evaluation of CAD with high accuracy, but delivers a significantly less effective radiation dose to patients compared to diagnostic invasive CA.

Time-course of "off-line" prefrontal rTMS effects--a PET study.

Low-frequency "off-line" repetitive transcranial magnetic stimulation (rTMS) over the course of several minutes has attained considerable attention as a research tool in cognitive neuroscience due to its ability to induce functional disruptions of brain areas. This disruptive rTMS effect is highly valuable for revealing a causal relationship between brain and behavior. However, its influence on remote interconnected areas and, more importantly, the duration of the induced neurophysiological effects, remain unknown. These aspects are critical for a study design in the context of cognitive neuroscience. In order to investigate these issues, 12 healthy male subjects underwent 8 H(2)(15)O positron emission tomography (PET) scans after application of long-train low-frequency rTMS to the right dorsolateral prefrontal cortex (DLPFC). Immediately after the stimulation train, regional cerebral blood flow (rCBF) increases were present under the stimulation site as well as in other prefrontal cortical areas, including the ventrolateral prefrontal cortex (VLPFC) ipsilateral to the stimulation site. The mean increases in rCBF returned to baseline within 9 min. The duration of this unilateral prefrontal rTMS effect on rCBF is of particular interest to those who aim to influence behavior in cognitive paradigms that use an "off-line" approach.

Transient epileptic opercular syndrome.

Ictal transient opercular syndrome is rarely observed in benign epilepsy with centro-temporal spikes in children, and even more rarely in epilepsia partialis continua and symptomatic focal status epilepticus in adults. Here we report the ictal and interictal neuroimaging and electrophysiological findings in an adult female suffering from discontinuous focal status epilepticus presenting as a transient opercular syndrome. This patient was unusual insofar as the discharges were strictly unilateral, i.e., that even with extensive neuroimaging no structural abnormalities could be found.

Lateralized and frequency-dependent effects of prefrontal rTMS on regional cerebral blood flow.

Repetitive transcranial magnetic stimulation (rTMS) is a means to study the function and connectivity of brain areas. The present study addressed the question of hemispheric asymmetry of frontal regions and aimed to further understand the acute effects of high- and low-frequency rTMS on regional cerebral blood flow (rCBF). Sixteen healthy right-handed men were imaged using H(2)(15)O positron emission tomography (PET) immediately after stimulation. High (10 Hz)- and low (1 Hz)-frequency suprathreshold short-duration rTMS was applied over either the left or right dorsolateral prefrontal cortex (DLPFC). Slow and fast rTMS applied over the left DLPFC significantly increased CBF in the stimulated area. Compared to baseline, slow rTMS induced a significant increase in CBF contralateral to the stimulation site, in the right caudate body and in the anterior cingulum. Furthermore, slow rTMS decreased CBF in the orbitofrontal cortex (OFC, ipsilateral to stimulation side). Fast rTMS applied over the right DLPFC was associated with increased activity at the stimulation site, in the bilateral orbitofrontal cortex and in the left medial thalamus compared to 1-Hz rTMS. These results show that rCBF changes induced by prefrontal rTMS differ upon hemisphere stimulated and vary with stimulation frequency. These differential neurophysiological effects of short-train rTMS with respect to side and frequency suggest hemisphere-dependent functional circuits of frontal cortico-subcortical areas.

H2(15)O or 13NH3 PET and electromagnetic tomography (LORETA) during partial status epilepticus.

The authors evaluated the feasibility and source localization utility of H2(15)O or 13NH3 PET and low-resolution electromagnetic tomography (LORETA) in three patients with partial status epilepticus (SE). Results were correlated with findings from intraoperative electrocorticographic recordings and surgical outcomes. PET studies of cerebral blood flow and noninvasive source modeling with LORETA using statistical nonparametric mapping provided useful information for localizing the ictal activity in patients with partial SE.

Exposure to pulse-modulated radio frequency electromagnetic fields affects regional cerebral blood flow.

We investigated the effects of radio frequency electromagnetic fields (RF EMF) similar to those emitted by mobile phones on waking regional cerebral blood flow (rCBF) in 12 healthy young men. Two types of RF EMF exposure were applied: a 'base-station-like' and a 'handset-like' signal. Positron emission tomography scans were taken after 30 min unilateral head exposure to pulse-modulated 900 MHz RF EMF (10 g tissue-averaged spatial peak-specific absorption rate of 1 W/kg for both conditions) and sham control. We observed an increase in relative rCBF in the dorsolateral prefrontal cortex on the side of exposure. The effect depended on the spectral power in the amplitude modulation of the RF carrier such that only 'handset-like' RF EMF exposure with its stronger low-frequency components but not the 'base-station-like' RF EMF exposure affected rCBF. This finding supports our previous observation that pulse modulation of RF EMF is necessary to induce changes in the waking and sleep EEG, and substantiates the notion that pulse modulation is crucial for RF EMF-induced alterations in brain physiology.

Attention and interhemispheric transfer: a behavioral and fMRI study.

When both detections and responses to visual stimuli are performed within one and the same hemisphere, manual reaction times (RTs) are faster than when the two operations are carried out in different hemispheres. A widely accepted explanation for this difference is that it reflects the time lost in callosal transmission. Interhemispheric transfer time can be estimated by subtracting RTs for uncrossed from RTs for crossed responses (crossed-uncrossed difference, or CUD). In the present study, we wanted to ascertain the role of spatial attention in affecting the CUD and to chart the brain areas whose activity is related to these attentional effects on interhemispheric transfer. To accomplish this, we varied the proportion of crossed and uncrossed trials in different blocks. With this paradigm subjects are likely to focus attention either on the hemifield contralateral to the responding hand (blocks with 80% crossed trials) or on the ipsilateral hemifield (blocks with 80% uncrossed trials). We found an inverse correlation between the proportion of crossed trials in a block and the CUD and this effect can be attributed to spatial attention. As to the imaging results, we found that in the crossed minus uncrossed subtraction, an operation that highlights the neural processes underlying interhemispheric transfer, there was an activation of the genu of the corpus callosum as well as of a series of cortical areas. In a further commonality analysis, we assessed those areas which were activated specifically during focusing of attention onto one hemifield either contra- or ipsilateral to the responding hand. We found an activation of a number of cortical and subcortical areas, notably, parietal area BA 7 and the superior colliculi. We believe that the main thrust of the present study is to have teased apart areas important in interhemispheric transmission from those involved in spatial attention.

Electromagnetic fields, such as those from mobile phones, alter regional cerebral blood flow and sleep and waking EEG.

Usage of mobile phones is rapidly increasing, but there is limited data on the possible effects of electromagnetic field (EMF) exposure on brain physiology. We investigated the effect of EMF vs. sham control exposure on waking regional cerebral blood flow (rCBF) and on waking and sleep electroencephalogram (EEG) in humans. In Experiment 1, positron emission tomography (PET) scans were taken after unilateral head exposure to 30-min pulse-modulated 900 MHz electromagnetic field (pm-EMF). In Experiment 2, night-time sleep was polysomnographically recorded after EMF exposure. Pulse-modulated EMF exposure increased relative rCBF in the dorsolateral prefrontal cortex ipsilateral to exposure. Also, pm-EMF exposure enhanced EEG power in the alpha frequency range prior to sleep onset and in the spindle frequency range during stage 2 sleep. Exposure to EMF without pulse modulation did not enhance power in the waking or sleep EEG. We previously observed EMF effects on the sleep EEG (A. A. Borbély, R. Huber, T. Graf, B. Fuchs, E. Gallmann and P. Achermann. Neurosci. Lett., 1999, 275: 207-210; R. Huber, T. Graf, K. A. Cote, L. Wittmann, E. Gallmann, D. Matter, J. Schuderer, N. Kuster, A. A. Borbély, and P. Achermann. Neuroreport, 2000, 11: 3321-3325), but the basis for these effects was unknown. The present results show for the first time that (1) pm-EMF alters waking rCBF and (2) pulse modulation of EMF is necessary to induce waking and sleep EEG changes. Pulse-modulated EMF exposure may provide a new, non-invasive method for modifying brain function for experimental, diagnostic and therapeutic purposes.

Selection of currently relevant memories by the human posterior medial orbitofrontal cortex.

We have demonstrated previously that patients producing spontaneous confabulations fail to suppress currently irrelevant memory traces, so that they act and think on the basis of a false, temporally displaced (past) reality. All spontaneous confabulators had anterior limbic damage, in particular of the orbitofrontal cortex and basal forebrain. These findings indicated that these structures are essential for distinguishing between mental representations of ongoing reality and currently irrelevant memories. In the present study, we used a similar experimental paradigm as in our clinical studies and H(2)(15)O positron emission tomography to explore the selection of currently relevant memories by the healthy human brain. Subjects were repeatedly presented with the same set of pictures, arranged in different order each time, and were requested to indicate picture recurrences within the runs. Thus, performance in the first run depended on new learning, whereas subsequent runs required the distinction between picture repetitions within the current run ("now") and previous picture presentations in earlier runs. Whereas initial learning activated medial temporal structures, subsequent runs provoked circumscribed posterior medial orbitofrontal activation. We suggest that this area is essential for sorting out mental associations that pertain to ongoing reality.

Hierarchical visual processing is dependent on the oculomotor system.

Using functional MRI and eye movement recordings we studied the processing of hierarchical stimuli. In agreement with others, we found a minor left hemispheric dominance during local and right dominance during global processing. When attention was directed locally, well-known oculomotor cortical areas were activated, and saccades were elicited in 41% of the trials. Their latencies were similar to pro-saccades. During global processing virtually no saccades occurred. These results suggest two different operational modes of attention. Attending to local features induces a shift of attention, which simultaneously computes a saccade on any level above the brainstem with a computational burden equal to reflexive saccades. Conversely, attending to global features induces an expansion of the focus of attention, which reinforces fixation.