Evaluation of [C]UCB-A positron emission tomography in human brains.

Background: In preclinical studies, the positron emission tomography (PET) imaging with [C]UCB-A provided promising results for imaging synaptic vesicle protein 2A (SV2A) as a proxy for synaptic density. This paper reports the first-in-human [C]UCB-A PET study to characterise its kinetics in healthy subjects and further evaluate SV2A-specific binding.

Results: Twelve healthy subjects underwent 90-min baseline [C]UCB-A scans with PET/MRI, with two subjects participating in an additional blocking scan with the same scanning procedure after a single dose of levetiracetam (1500 mg).

Synaptic density patterns in early Alzheimer's disease assessed by independent component analysis.

Synaptic loss is a primary pathology in Alzheimer's disease and correlates best with cognitive impairment as found in studies. Previously, we observed reductions of synaptic density with [C]UCB-J PET (radiotracer for synaptic vesicle protein 2A) throughout the neocortex and medial temporal brain regions in early Alzheimer's disease. In this study, we applied independent component analysis to synaptic vesicle protein 2A-PET data to identify brain networks associated with cognitive deficits in Alzheimer's disease in a blinded data-driven manner.

Linking resting-state network fluctuations with systems of coherent synaptic density: A multimodal fMRI and C-UCB-J PET study.

Resting-state network (RSN) connectivity is a widely used measure of the brain's functional organization in health and disease; however, little is known regarding the underlying neurophysiology of RSNs. The aim of the current study was to investigate associations between RSN connectivity and synaptic density assessed using the synaptic vesicle glycoprotein 2A radioligand C-UCB-J PET. Independent component analyses (ICA) were performed on resting-state fMRI and PET data from 34 healthy adult participants (16F, mean age: 46 ± 15 years) to identify RSNs of interest (default-mode, right frontoparietal executive-control, salience, and sensorimotor networks) and select sources of C-UCB-J variability (medial prefrontal, striatal, and medial parietal).

Reversal of synapse loss in Alzheimer mouse models by targeting mGluR5 to prevent synaptic tagging by C1Q.

Microglia-mediated synaptic loss contributes to the development of cognitive impairments in Alzheimer's disease (AD). However, the basis for this immune-mediated attack on synapses remains to be elucidated. Treatment with the metabotropic glutamate receptor 5 (mGluR5) silent allosteric modulator (SAM), BMS-984923, prevents β-amyloid oligomer-induced aberrant synaptic signaling while preserving physiological glutamate response.

Brain pharmacokinetics of two BBB penetrating bispecific antibodies of different size.

Background: Transferrin receptor (TfR1) mediated enhanced brain delivery of antibodies have been studied extensively in preclinical settings. However, the brain pharmacokinetics, i.e.

Identifying brain networks in synaptic density PET (C-UCB-J) with independent component analysis.

Background: The human brain is inherently organized into distinct networks, as reported widely by resting-state functional magnetic resonance imaging (rs-fMRI), which are based on blood-oxygen-level-dependent (BOLD) signal fluctuations. C-UCB-J PET maps synaptic density via synaptic vesicle protein 2A, which is a more direct structural measure underlying brain networks than BOLD rs-fMRI.

Methods: The aim of this study was to identify maximally independent brain source networks, i.

Quantification of SV2A Binding in Rodent Brain Using [F]SynVesT-1 and PET Imaging.

Purpose: Synapse loss is a hallmark of Alzheimer's disease (AD) and correlates with cognitive decline. The validation of a noninvasive in vivo imaging approach to quantify synapse would greatly facilitate our understanding of AD pathogenesis and assist drug developments for AD. As animal models of neurodegenerative and neuropsychiatric disorders play a critical role in the drug discovery and development process, a robust, objective, and translational method for quantifying therapeutic drug efficacy in animal models will facilitate the drug development process.

Fluorine-18-Labeled Antibody Ligands for PET Imaging of Amyloid-β in Brain.

Antibodies are attractive as radioligands due to their outstanding specificity and high affinity, but their inability to cross the blood-brain barrier (BBB) limits their use for CNS targets. To enhance brain distribution, amyloid-β (Aβ) antibodies were fused to a transferrin receptor (TfR) antibody fragment, enabling receptor mediated transport across the BBB. The aim of this study was to label these bispecific antibodies with fluorine-18 and use them for Aβ PET imaging.

High detection sensitivity with antibody-based PET radioligand for amyloid beta in brain.

PET imaging of amyloid-beta (Aβ) deposits in brain has become an important aid in Alzheimer's disease diagnosis, and an inclusion criterion for patient enrolment into clinical trials of new anti-Aβ treatments. Available PET radioligands visualizing Aβ bind to insoluble fibrils, i.e.

Antibody-Based In Vivo PET Imaging Detects Amyloid-β Reduction in Alzheimer Transgenic Mice After BACE-1 Inhibition.

Visualization of amyloid-β (Aβ) pathology with PET has become an important tool for making a specific clinical diagnosis of Alzheimer disease (AD). However, the available amyloid PET radioligands, such as C-Pittsburgh compound B, reflect levels of insoluble Aβ plaques but do not capture soluble and protofibrillar Aβ forms. Furthermore, the plaque load appears to be fairly static during clinical stages of AD and may not be affected by Aβ-reducing treatments.

Astroglial Responses to Amyloid-Beta Progression in a Mouse Model of Alzheimer's Disease.

Purpose: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by amyloid-beta (Aβ) deposition, hyperphosphorylation of tau, and neuroinflammation. Astrocytes, the most abundant glial cell type in the nervous system, respond to neurodegenerative disorders through astrogliosis, i.e.

Pharmacokinetics, biodistribution and brain retention of a bispecific antibody-based PET radioligand for imaging of amyloid-β.

Monoclonal antibodies (mAbs) have not been used as positron emission tomography (PET) ligands for in vivo imaging of the brain because of their limited passage across the blood-brain barrier (BBB). However, due to their high affinity and specificity, mAbs may be an attractive option for brain PET if their brain distribution can be facilitated. In the present study, a F(ab') fragment of the amyloid-beta (Aβ) protofibril selective mAb158 was chemically conjugated to the transferrin receptor (TfR) antibody 8D3 to enable TfR mediated transcytosis across the BBB.

Efficient and inexpensive transient expression of multispecific multivalent antibodies in Expi293 cells.

Background: Immunotherapy is a very fast expanding field within drug discovery and, hence, rapid and inexpensive expression of antibodies would be extremely valuable. Antibodies are, however, difficult to express. Multifunctional antibodies with additional binding domains further complicate the expression.

A bispecific Tribody PET radioligand for visualization of amyloid-beta protofibrils - a new concept for neuroimaging.

Antibodies are highly specific for their target molecules, but their poor brain penetrance has restricted their use as PET ligands for imaging of targets within the CNS. The aim of this study was to develop an antibody-based radioligand, using the Tribody format, for PET imaging of soluble amyloid-beta (Aβ) protofibrils, which are suggested to cause neurodegeneration in Alzheimer's disease. Antibodies, even when expressed in smaller engineered formats, are large molecules that do not enter the brain in sufficient amounts for imaging purposes.

Bivalent Brain Shuttle Increases Antibody Uptake by Monovalent Binding to the Transferrin Receptor.

The blood-brain barrier (BBB) is an obstacle for antibody passage into the brain, impeding the development of immunotherapy and antibody-based diagnostics for brain disorders. In the present study, we have developed a brain shuttle for active transport of antibodies across the BBB by receptor-mediated transcytosis. We have thus recombinantly fused two single-chain variable fragments (scFv) of the transferrin receptor (TfR) antibody 8D3 to the light chains of mAb158, an antibody selectively binding to Aβ protofibrils, which are involved in the pathogenesis of Alzheimer's disease (AD).

Brain mGluR5 in mice with amyloid beta pathology studied with in vivo [C]ABP688 PET imaging and ex vivo immunoblotting.

Alzheimer's disease (AD) is characterized by aggregation of amyloid beta (Aβ) into insoluble plaques. Intermediates, Aβ oligomers (Aβo), appear to be the mechanistic cause of disease. The de facto PET AD ligand, [C]PIB, binds and visualizes Aβ plaque load, which does not correlate well with disease severity.

Antibody-based PET imaging of amyloid beta in mouse models of Alzheimer's disease.

Owing to their specificity and high-affinity binding, monoclonal antibodies have potential as positron emission tomography (PET) radioligands and are currently used to image various targets in peripheral organs. However, in the central nervous system, antibody uptake is limited by the blood-brain barrier (BBB). Here we present a PET ligand to be used for diagnosis and evaluation of treatment effects in Alzheimer's disease.

Effects of specific multi-nutrient enriched diets on cerebral metabolism, cognition and neuropathology in AβPPswe-PS1dE9 mice.

Recent studies have focused on the use of multi-nutrient dietary interventions in search of alternatives for the treatment and prevention of Alzheimer's disease (AD). In this study we investigated to which extent long-term consumption of two specific multi-nutrient diets can modulate AD-related etiopathogenic mechanisms and behavior in 11-12-month-old AβPPswe-PS1dE9 mice. Starting from 2 months of age, male AβPP-PS1 mice and wild-type littermates were fed either a control diet, the DHA+EPA+UMP (DEU) diet enriched with uridine monophosphate (UMP) and the omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), or the Fortasyn® Connect (FC) diet enriched with the DEU diet plus phospholipids, choline, folic acid, vitamins and antioxidants.