Natalie Nelissen

18F-flutemetamol amyloid imaging in Alzheimer disease and mild cognitive impairment: a phase 2 trial.

The most widely studied positron emission tomography ligand for in vivo β‐amyloid imaging is 11C‐Pittsburgh compound B (11C‐PIB). Its availability, however, is limited by the need for an on‐site cyclotron. Validation of the 18F‐labeled PIB derivative 18F‐flutemetamol could significantly enhance access to this novel technology.

Phase 1 Study of the Pittsburgh Compound B Derivative 18F-Flutemetamol in Healthy Volunteers and Patients with Probable Alzheimer Disease

11C-Pittsburgh compound B (PiB) marks Aβ amyloidosis, a key pathogenetic process in Alzheimer disease (AD). The use of 11C-PiB is limited to centers with a cyclotron. Development of the 18F-labeled thioflavin derivative of PiB, 18F-flutemetamol, could hugely increase the availability of this new technology. The aims of this phase 1 study were to perform brain kinetic modeling of 18F-flutemetamol, optimize the image acquisition procedure, and compare methods of analysis (step 1) and to compare 18F-flutemetamol brain retention in AD patients versus healthy controls in a proof-of-concept study (steps 1 and 2). Methods: In step 1, 3 AD patients (Mini-Mental State Examination, 22–24) and 3 elderly healthy controls were scanned dynamically during windows of 0–90, 150–180, and 220–250 min after injection of approximately 180 MBq of 18F-flutemetamol, with arterial sampling. We compared different analysis methods (compartmental modeling, Logan graphical analysis, and standardized uptake value ratios) and determined the optimal acquisition window for step 2. In step 2, 5 AD patients (Mini-Mental State Examination, 20–26) and 5 elderly healthy controls were scanned from 80 to 170 min after injection. To determine overall efficacy, steps 1 and 2 were pooled and standardized uptake value ratios were calculated using cerebellar cortex as a reference region. Results: No adverse events were reported. There was a strong correlation between uptake values obtained with the different analysis methods. From 80 min after injection onward, the ratio of neocortical to cerebellar uptake was maximal and only marginally affected by scan start time or duration. AD patients showed significantly increased standardized uptake value ratios in neocortical association zones and striatum, compared with healthy controls, whereas uptake in white matter, cerebellum, and pons did not differ between groups. Two AD patients were 18F-flutemetamol–negative and 1 healthy control was 18F-flutemetamol–positive. Conclusion: 18F-flutemetamol uptake can be readily quantified. This phase 1 study warrants further studies to validate this 18F-labeled derivative of PiB as a biomarker for Aβ amyloidosis.

Whole-Body Biodistribution and Radiation Dosimetry of 18F-GE067: A Radioligand for In Vivo Brain Amyloid Imaging

We have characterized the biodistribution and dosimetry of 18F-3′-F-6-OH-BTA1 (18F-GE067), a newly developed radioligand to visualize and quantify amyloid burden, in healthy elderly human subjects. Methods: Six subjects (5 men and 1 woman; age range, 51–74 y) underwent dynamic whole-body PET/CT for 6 h after a bolus injection of 18F-GE067. Source organs were delineated on PET/CT. Individual organ doses and effective doses were determined. Results: No adverse events or clinically significant changes were observed. 18F-GE067 is excreted predominantly through the hepatobiliary system. The gallbladder, upper large intestine, and small intestine are the organs with the highest absorbed dose (average, 287, 173, and 155 μGy/MBq, respectively). The mean effective dose was 33.8 ± 3.4 μSv/MBq, a dose comparable to that of many other 18F-labeled radiopharmaceuticals. Conclusion: The estimated effective dose of 18F-GE067 for PET amyloid imaging was acceptable (class II-b defined by the World Health Organization), and relatively low variability between subjects was observed.

Correlations of interictal FDG-PET metabolism and ictal SPECT perfusion changes in human temporal lobe epilepsy with hippocampal sclerosis

BACKGROUND The pathophysiological role of the extensive interictal cerebral hypometabolism in complex partial seizures (CPS) in refractory mesial temporal lobe epilepsy with hippocampal sclerosis (mTLE-HS) is poorly understood. Our aim was to study ictal-interictal SPECT perfusion versus interictal fluorodeoxyglucose (FDG)-PET metabolic patterns. METHODS Eleven adults with refractory unilateral mTLE-HS, who were rendered seizure free after epilepsy surgery, were included. All had an interictal FDG-PET and an interictal and ictal perfusion SPECT scan. FDG-PET data were reconstructed using an anatomy-based reconstruction algorithm, which corrected for partial volume effects, and analyzed semi-quantitatively after normalization to white matter activity. Using Statistical Parametric Mapping (SPM), we compared interictal metabolism of the patient group with a control group. We correlated metabolic with ictal perfusion changes in the patient group. RESULTS Global cerebral grey matter glucose metabolism in patients was decreased 10-25% compared with control subjects. Interictal PET hypometabolism and ictal SPECT hypoperfusion were maximal in the ipsilateral frontal lobe. Ictal frontal lobe hypoperfusion was associated with crossed cerebellar diaschisis. The ipsilateral temporal lobe showed maximal ictal hyperperfusion and interictal hypometabolism, which was relatively mild compared with the degree of hypometabolism affecting the frontal lobes. CONCLUSION Interictal hypometabolism in mTLE-HS was greatest in the ipsilateral frontal lobe and represented a seizure-related dynamic process in view of further ictal decreases. Crossed cerebellar diaschisis suggested that there is a strong ipsilateral frontal lobe inhibition during CPS. We speculate that surround inhibition in the frontal lobe is a dynamic defense mechanism against seizure propagation, and may be responsible for functional deficits observed in mTLE.

Noninvasive associative plasticity induction in a corticocortical pathway of the human brain.

Coincident pairing of presynaptic and postsynaptic activity selectively strengthens synaptic connections, a key mechanism underlying cortical plasticity. Using paired associative transcranial magnetic stimulation (TMS), we demonstrate selective potentiation of physiological connectivity between two human brain regions, ventral premotor cortex (PMv) and primary motor cortex (M1) after repeated paired-pulse TMS of PMv and M1. The effect was anatomically specific: paired stimulation of the presupplementary motor area and M1 did not induce changes in PMv–M1 pathway connectivity. The effect was dependent on stimulation order: repeated stimulation of PMv before M1 led to strengthening of the PMv–M1 pathway, while repeated stimulation of M1 before PMv diminished the strength of the PMv–M1 pathway. The expression of the change in the pathway depended on the cognitive state of the subject at the time of testing: when the subject was tested at rest, paired PMv–M1 stimulation led to an increased inhibitory influence of PMv over M1, but when the subject was tested while engaged in a visuomotor task, PMv–M1 stimulation led to an increased facilitatory influence of PMv over M1. Plasticity evolved rapidly, lasted for at least 1 h, and began to reverse 3 h after intervention.

Frontal and parietal cortical interactions with distributed visual representations during selective attention and action selection.

Using multivoxel pattern analysis (MVPA), we studied how distributed visual representations in human occipitotemporal cortex are modulated by attention and link their modulation to concurrent activity in frontal and parietal cortex. We detected similar occipitotemporal patterns during a simple visuoperceptual task and an attention-to-working-memory task in which one or two stimuli were cued before being presented among other pictures. Pattern strength varied from highest to lowest when the stimulus was the exclusive focus of attention, a conjoint focus, and when it was potentially distracting. Although qualitatively similar effects were seen inside regions relatively specialized for the stimulus category and outside, the former were quantitatively stronger. By regressing occipitotemporal pattern strength against activity elsewhere in the brain, we identified frontal and parietal areas exerting top-down control over, or reading information out from, distributed patterns in occipitotemporal cortex. Their interactions with patterns inside regions relatively specialized for that stimulus category were higher than those with patterns outside those regions and varied in strength as a function of the attentional condition. One area, the frontal operculum, was distinguished by selectively interacting with occipitotemporal patterns only when they were the focus of attention. There was no evidence that any frontal or parietal area actively inhibited occipitotemporal representations even when they should be ignored and were suppressed. Using MVPA to decode information within these frontal and parietal areas showed that they contained information about attentional context and/or readout information from occipitotemporal cortex to guide behavior but that frontal regions lacked information about category identity.

Gesture Discrimination in Primary Progressive Aphasia: The Intersection between Gesture and Language Processing Pathways

The issue of the relationship between language and gesture processing and the partial overlap of their neural representations is of fundamental importance to neurology, psychology, and social sciences. Patients suffering from primary progressive aphasia, a clinical syndrome characterized by comparatively isolated language deficits, may provide direct evidence for anatomical and functional association between specific language deficits and gesture discrimination deficits. A consecutive series of 16 patients with primary progressive aphasia and 16 matched control subjects participated. Our nonverbal gesture discrimination task consisted of 19 trials. In each trial, participants observed three video clips showing the same gesture performed correctly in one clip and incorrectly in the other two. Subjects had to indicate which of the three versions was correct. Language and gesture production were evaluated by means of conventional tasks. All participants underwent high-resolution structural and diffusion tensor magnetic resonance imaging. Ten of the primary progressive aphasia patients showed a significant deficit on the nonverbal gesture discrimination task. A factor analysis revealed that this deficit clustered with gesture imitation, word and pseudoword repetition, and writing-to-dictation. Individual scores on this cluster correlated with volume in the left anterior inferior parietal cortex extending into the posterior superior temporal gyrus. Probabilistic tractography indicated this region comprised the cortical relay station of the indirect pathway connecting the inferior frontal gyrus and the superior temporal cortex. Thus, the left perisylvian temporoparietal area may underpin verbal imitative behavior, gesture imitation, and gesture discrimination indicative of a partly shared neural substrate for language and gesture resonance.

The associative-semantic network for words and pictures: Effective connectivity and graph analysis

Explicit associative-semantic processing of words and pictures activates a distributed set of brain areas that has been replicated across a wide range of studies. We applied graph analysis to examine the structure of this network. We determined how the left ventral occipitotemporal transition zone (vOT) was connected to word-specific areas. A modularity analysis discerned four communities: one corresponded to the classical perisylvian language system, including superior temporal sulcus (STS), middle temporal gyrus (GTm) and pars triangularis of the inferior frontal gyrus (GFi), among other nodes. A second subsystem consisted of vOT and anterior fusiform gyrus along with hippocampus and intraparietal sulcus. The two subsystems were linked through a unique connection between vOT and GTm, which were hubs with a high betweenness centrality compared to STS and GFi which had a high local clustering coefficient. Graph analysis reveals novel insights into the structure of the network for associative-semantic processing.

Predictive decision making driven by multiple time-linked reward representations in the anterior cingulate cortex

In many natural environments the value of a choice gradually gets better or worse as circumstances change. Discerning such trends makes predicting future choice values possible. We show that humans track such trends by comparing estimates of recent and past reward rates, which they are able to hold simultaneously in the dorsal anterior cingulate cortex (dACC). Comparison of recent and past reward rates with positive and negative decision weights is reflected by opposing dACC signals indexing these quantities. The relative strengths of time-linked reward representations in dACC predict whether subjects persist in their current behaviour or switch to an alternative. Computationally, trend-guided choice can be modelled by using a reinforcement-learning mechanism that computes a longer-term estimate (or expectation) of prediction errors. Using such a model, we find a relative predominance of expected prediction errors in dACC, instantaneous prediction errors in the ventral striatum and choice signals in the ventromedial prefrontal cortex.

Self-Other Mergence in the Frontal Cortex during Cooperation and Competition

Summary To survive, humans must estimate their own ability and the abilities of others. We found that, although people estimated their abilities on the basis of their own performance in a rational manner, their estimates of themselves were partly merged with the performance of others. Reciprocally, their ability estimates for others also reflected their own, as well as the others’, performance. Self-other mergence operated in a context-dependent manner: interacting with high or low performers, respectively, enhanced and diminished own ability estimates in cooperative contexts, but the opposite occurred in competitive contexts. Self-other mergence not only influenced subjective evaluations, it also affected how people subsequently objectively adjusted their performance. Perigenual anterior cingulate cortex tracked one’s own performance. Dorsomedial frontal area 9 tracked others’ performances, but also integrated contextual and self-related information. Self-other mergence increased with the strength of self and other representations in area 9, suggesting it carries interdependent representations of self and other.