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Abstract Background Hijacking the transferrin receptor (TfR) is an effective strategy to transport amyloid-beta (Aβ) immuno-positron emission tomography (immunoPET) ligands across the blood–brain barrier (BBB). Such ligands are more sensitive and specific than small-molecule ligands at detecting Aβ pathology in mouse models of Alzheimer’s disease (AD). This study aimed to determine if this strategy would be as sensitive in rats and to assess how TfR affinity affects BBB transport of bispecific immunoPET radioligands. Methods Two affinity variants of the rat TfR antibody, OX26, were chemically conjugated to a F(ab′)2 fragment of the anti-Aβ antibody, bapineuzumab (Bapi), to generate two bispecific fusion proteins: OX265-F(ab′)2-Bapi and OX2676-F(ab′)2-Bapi. Pharmacokinetic analyses were performed 4 h and 70 h post-injection of radioiodinated fusion proteins in wild-type (WT) rats. [124I]I-OX265-F(ab′)2-Bapi was administered to TgF344-AD and WT rats for in vivo PET imaging. Ex vivo distribution of injected [124I]I-OX265-F(ab′)2-Bapi and Aβ pathology were assessed. Results More [125I]I-OX265-F(ab′)2-Bapi was taken up into the brain 4 h post-administration than [124I]I-OX2676-F(ab′)2-Bapi. [124I]I-OX265-F(ab′)2-Bapi PET visualized Aβ pathology with significantly higher signals in the TgF344-AD rats than in the WT littermates without Aβ pathology. The PET signals significantly correlated with Aβ levels in AD animals. Conclusion Affinity to TfR affects how efficiently a TfR-targeting bispecific fusion protein will cross the BBB, such that the higher-affinity bispecific fusion protein crossed the BBB more efficiently. Furthermore, bispecific immunoPET imaging of brain Aβ pathology using TfR-mediated transport provides good imaging contrast between TgF344-AD and WT rats, suggesting that this immunoPET strategy has the potential to be translated to higher species.

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Abstract The effect of magnetic field ripple on tokamak plasma without turbulence is studied numerically and augmented with a reduced analytical model that includes neoclassical processes in the presence of non-axisymmetric perturbation and stochastic transport. For this study, a magnetic field ripple perturbation has been implemented in the GYSELA gyrokinetic code. This implementation has been verified thanks to a test of toroidal angular momentum conservation. The GYSELA code was then successfully benchmarked against the NEO code, which solves the drift kinetic equation, and against the reduced model in the collisionality range ν ⋆ ∈ [0.05–0.5] for several amplitudes of the magnetic ripple. An observation, shared by the model, the NEO code and GYSELA simulations is that the thermal drive of the mean poloidal velocity—measured by the k V P coefficient—decreases sharply for large yet experimentally relevant magnetic ripple amplitudes, and may even change sign.

AbstractThere is ongoing debate regarding the extent to which human cortices are specialized for processing a given sensory input versus a given type of information, independently of the sensory source. Many neuroimaging and electrophysiological studies have reported that primary and extrastriate visual cortices respond to tactile and auditory stimulation, in addition to visual inputs, suggesting these cortices are intrinsically multisensory. In particular for tactile responses, few studies have proven neuronal processes in visual cortex in humans. Here, we assessed tactile responses in both low-level and extrastriate visual cortices using electrocorticography recordings in a human participant. Specifically, we observed significant spectral power increases in the high frequency band (30–100 Hz) in response to tactile stimuli, reportedly associated with spiking neuronal activity, in both low-level visual cortex (i.e. V2) and in the anterior part of the lateral occipital–temporal cortex. These sites were both involved in processing tactile information and responsive to visual stimulation. More generally, the present results add to a mounting literature in support of task-sensitive and sensory-independent mechanisms underlying functions like spatial, motion, and self-processing in the brain and extending from higher-level as well as to low-level cortices.

Preoperative clinical magnetic resonance imaging (MRI) protocols for gliomas, brain tumors with dismal outcomes due to their infiltrative properties, still rely on conventional structural MRI, which does not deliver information on tumor genotype and is limited in the delineation of diffuse gliomas. The GliMR COST action wants to raise awareness about the state of the art of advanced MRI techniques in gliomas and their possible clinical translation or lack thereof. This review describes current methods, limits, and applications of advanced MRI for the preoperative assessment of glioma, summarizing the level of clinical validation of different techniques. In this first part, we discuss dynamic susceptibility contrast and dynamic contrast‐enhanced MRI, arterial spin labeling, diffusion‐weighted MRI, vessel imaging, and magnetic resonance fingerprinting. The second part of this review addresses magnetic resonance spectroscopy, chemical exchange saturation transfer, susceptibility‐weighted imaging, MRI‐PET, MR elastography, and MR‐based radiomics applications.Evidence Level: 3Technical Efficacy: Stage 2

Inflammation is a pathophysiological hallmark of many diseases of the brain. Specific imaging of cells and molecules that contribute to cerebral inflammation is therefore highly desirable, both for research and in clinical application. The 18 kDa translocator protein (TSPO) has been established as a suitable target for the detection of activated microglia/macrophages. A number of novel TSPO ligands have been developed recently. Here, we evaluated the high affinity TSPO ligand DPA-714 as a marker of brain inflammation in two independent animal models. For the first time, the specificity of radiolabeled DPA-714 for activated microglia/macrophages was studied in a rat model of epilepsy (induced using Kainic acid) and in a mouse model of stroke (transient middle cerebral artery occlusion, tMCAO) using high-resolution autoradiography and immunohistochemistry. Additionally, cold-compound blocking experiments were performed and changes in blood-brain barrier (BBB) permeability were determined. Target-to-background ratios of 2 and 3 were achieved in lesioned vs. unaffected brain tissue in the epilepsy and tMCAO models, respectively. In both models, ligand uptake into the lesion corresponded well with the extent of Ox42- or Iba1-immunoreactive activated microglia/macrophages. In the epilepsy model, ligand uptake was almost completely blocked by pre-injection of DPA-714 and FEDAA1106, another high-affinity TSPO ligand. Ligand uptake was independent of the degree of BBB opening and lesion size in the stroke model. We provide further strong evidence that DPA-714 is a specific ligand to image activated microglia/macrophages in experimental models of brain inflammation.

The 16p11.2 600 kb BP4-BP5 deletion and duplication syndromes have been associated with developmental delay; autism spectrum disorders; and reciprocal effects on the body mass index, head circumference and brain volumes. Here, we explored these relationships using novel engineered mouse models carrying a deletion (Del/+) or a duplication (Dup/+) of the Sult1a1-Spn region homologous to the human 16p11.2 BP4-BP5 locus. On a C57BL/6N inbred genetic background, Del/+ mice exhibited reduced weight and impaired adipogenesis, hyperactivity, repetitive behaviors, and recognition memory deficits. In contrast, Dup/+ mice showed largely opposite phenotypes. On a F1 C57BL/6N × C3B hybrid genetic background, we also observed alterations in social interaction in the Del/+ and the Dup/+ animals, with other robust phenotypes affecting recognition memory and weight. To explore the dosage effect of the 16p11.2 genes on metabolism, Del/+ and Dup/+ models were challenged with high fat and high sugar diet, which revealed opposite energy imbalance. Transcriptomic analysis revealed that the majority of the genes located in the Sult1a1-Spn region were sensitive to dosage with a major effect on several pathways associated with neurocognitive and metabolic phenotypes. Whereas the behavioral consequence of the 16p11 region genetic dosage was similar in mice and humans with activity and memory alterations, the metabolic defects were opposite: adult Del/+ mice are lean in comparison to the human obese phenotype and the Dup/+ mice are overweight in comparison to the human underweight phenotype. Together, these data indicate that the dosage imbalance at the 16p11.2 locus perturbs the expression of modifiers outside the CNV that can modulate the penetrance, expressivity and direction of effects in both humans and mice. Author Summary The 16p11.2 BP4-BP5 deletion and duplication syndromes are frequent copy number variants in humans, and are associated with developmental delay and autism spectrum disorders, with a reciprocal effect on head circumference and body mass index. Here we explored gene dosage effect in mouse models and found that the deletion and duplication induced opposite behavioral phenotypes. Notably, we observed that some behavioral phenotypes, such as social interaction, were sensitive to the genetic background. For the metabolism, the energy imbalance and adipocyte phenotypes were mirrored in the deletion and duplication carriers but opposite to the human phenotypes, the deletion mouse carriers were lean whereas the individuals with the deletion were obese. The main cause of the phenotypic features is the copy number variation of the 16p11.2 region with many genetic pathways altered in the striatum and the liver. Thus the final consequences of the rearrangement are likely governed by the interplay between many cellular pathways in both human cases and mouse models.