Defining repetitive behaviours in frontotemporal dementia.

Repetitive behaviours are common manifestations of frontotemporal dementia (FTD). Patients with FTD exhibit various types of repetitive behaviours with unique behavioural and cognitive substrates, including compulsivity, lack of impulse control, stereotypy and hoarding. Other sources of repetitive behaviours, such as restrictive interests and insistence on sameness, may also be seen in FTD. Although repetitive behaviours are highly prevalent and potentially discriminatory in this population, their expression varies widely between patients, and the field lacks consensus about the classification of these behaviours. Terms used to describe repetitive behaviours in FTD are highly heterogeneous and may lack precise definitions. This lack of harmonization of the definitions for distinct forms of repetitive behaviour limits the ability to differentiate between pathological behaviours and impedes understanding of their underlying mechanisms. This review examines established definitions of well-characterized repetitive behaviours in other neuropsychiatric disorders and proposes operational definitions applicable to patients with FTD. Building on extant models of repetitive behaviours in non-human and lesion work and models of social behavioural changes in FTD, we describe the potential neurocognitive bases for the emergence of different types of repetitive behaviours in FTD and their potential perpetuation by a predisposition towards habit formation. Finally, examples of distinct therapeutic approaches for different forms of repetitive behaviours are highlighted, along with future directions to accurately classify, measure and treat these symptoms when they impair quality of life.

Cell-Surface-Retained Peptide Additives for the Cytosolic Delivery of Functional Proteins.

The delivery of functional proteins remains a major challenge in advancing biological and pharmaceutical sciences. Herein, we describe a powerful, simple, and highly effective strategy for the intracellular delivery of functional cargoes. Previously, we demonstrated that cell-penetrating peptide (CPP) additives equipped with electrophilic thiol-reactive moieties temporarily attach to the cellular membrane, thereby facilitating the cellular uptake of protein- and antibody-CPP cargoes through direct membrane transduction at low concentrations. Now, we hypothesize that CPP-additives with an increased retention on the cellular membrane will further enhance intracellular uptake. We discovered that adding a small hydrophobic peptide sequence to an arginine-rich electrophilic CPP-additive further improved the uptake of protein-CPP conjugates, whereas larger hydrophobic anchors showed increased cytotoxicity. Cell viability and membrane integrity measurements, structure-activity relationship studies, and quantitative evaluation of protein-CPP uptake revealed important design principles for cell-surface-retained CPP-additives. These investigations allowed us to identify a nontoxic, thiol-reactive CPP-additive containing the hydrophobic ILFF sequence, which can deliver fluorescent model proteins at low micromolar concentrations. This hydrophobic CPP-additive allowed the addition of protein cargoes for intracellular delivery after initial additive incubation. Time-lapse fluorescence microscopy and membrane tension analysis of cells treated with fluorescent ILFF-CPP-additives supported the claim of increased cell surface retention and suggested that the protein-CPP cargoes enter the cell through a mechanism involving lowered cell membrane tension. Finally, we demonstrated that our newly engineered hydrophobic CPP-additive enabled the uptake of a functional macrocyclic peptidic MDM2-inhibitor and a recombinant genome editing protein. This indicates that the developed hydrophobic CPP-additive holds promise as a tool to enhance the intracellular delivery of peptide and protein cargoes.

Dimeric Metal-Salphen Complexes Which Target Multimeric G-Quadruplex DNA.

G-Quadruplex DNA structures have attracted increasing attention due to their biological roles and potential as targets for the development of new drugs. While most guanine-rich sequences in the genome have the potential to form monomeric G-quadruplexes, certain sequences have enough guanine-tracks to give rise to multimeric quadruplexes. One of these sequences is the human telomere where tandem repeats of TTAGGG can lead to the formation of two or more adjacent G-quadruplexes. Herein we report on the modular synthesis via click chemistry of dimeric metal-salphen complexes (with NiII and PtII) bridged by either polyether or peptide linkers. We show by circular dichroism (CD) spectroscopy that they generally have higher selectivity for dimeric vs monomeric G-quadruplexes. The emissive properties of the PtII-salphen dimeric complexes have been used to study their interactions with monomeric and dimeric G-quadruplexes in vitro as well as to study their cellular uptake and localization.

Accuracy of PET quantification in [68Ga]Ga-pentixafor PET/MR imaging of carotid plaques.

AIM: The aim of this study was to evaluate and correct for partial-volume-effects (PVE) on [68Ga]Ga-Pentixafor uptake in atherosclerotic plaques of the carotid arteries, and the impact of ignoring bone in MR-based attenuation correction (MR-AC). METHODS: Twenty [68Ga]Ga-pentixafor PET/MR examinations including a high-resolution T2-TSE MR of the neck were included in this study. Carotid plaques located at the carotid bifurcation were delineated and the anatomical information was used for partial-volume-correction (PVC). Mean and max tissue-to-background ratios (TBR) of the [68Ga]Ga-Pentixafor uptake were compared for standard and PVC-PET images. A potential influence of ignoring bone in MR-AC was assessed in a subset of the data reconstructed after incorporating bone into MR-AC and a subsequent comparison of standardized-uptake values (SUV). RESULTS: In total, 34 atherosclerotic plaques were identified. Following PVC, mean and max TBR increased by 77 and 95%, respectively, when averaged across lesions. When accounting for bone in the MR-AC, SUV of plaque changed by 0.5%. CONCLUSION: Quantitative readings of [68Ga]Ga-pentixafor uptake in plaques are strongly affected by PVE, which can be reduced by PVC. Including bone information into the MR-AC yielded no clinically relevant effect on tracer quantification.

Structure-Uptake Relationship Study of DABCYL Derivatives Linked to Cyclic Cell-Penetrating Peptides for Live-Cell Delivery of Synthetic Proteins.

Modifying cyclic cell-penetrating deca-arginine (cR10) peptides with 4-(4-dimethylaminophenylazo)benzoic acid (DABCYL) improves the uptake efficiency of synthetic ubiquitin (Ub) cargoes into living cells. To probe the role of the DABCYL moiety, we performed time-lapse microscopy and fluorescence lifetime imaging microscopy (FLIM) of fluorescent DABCYL-R10 to evaluate the impact on cell entry by the formation of nucleation zones. Furthermore, we performed a structure-uptake relationship study with 13 DABCYL derivatives coupled to CPP to examine their effect on the cell-uptake efficiency when conjugated to mono-Ub through disulfide linkages. Our results show that through structure variations of the DABCYL moiety alone we could reach, at nanomolar concentration, an additional threefold increase in the cytosolic delivery of Ub, which will enable studies on various intracellular processes related to Ub signaling.

Stereoselective Self-Assembly of DNA Binding Helicates Directed by the Viral ß-Annulus Trimeric Peptide Motif.

Combining coordination chemistry and peptide engineering offers extraordinary opportunities for developing novel molecular (supra)structures. Here, we demonstrate that the ß-annulus motif is capable of directing the stereoselective assembly of designed peptides containing 2,2'-bipyridine ligands into parallel three-stranded chiral peptide helicates, and that these helicates selectively bind with high affinity to three-way DNA junctions.

Dynamic Stereoselection of Peptide Helicates and Their Selective Labeling of DNA Replication Foci in Cells*.

Although largely overlooked in peptide engineering, coordination chemistry offers a new set of interactions that opens unexplored design opportunities for developing complex molecular structures. In this context, we report new artificial peptide ligands that fold into chiral helicates in the presence of labile metal ions such as FeII and CoII . Heterochiral ß-turn-promoting sequences encode the stereoselective folding of the peptide ligands and define the physicochemical properties of their corresponding metal complexes. Circular dichroism and NMR spectroscopy in combination with computational methods allowed us to identify and determine the structure of two isochiral ΛΛ-helicates, folded as topological isomers. Finally, in addition to the in-vitro characterization of their selective binding to DNA three-way junctions, cell-microscopy experiments demonstrated that a rhodamine-labeled FeII helicate was internalized and selectively stains DNA replication factories in functional cells.

Data-driven, projection-based respiratory motion compensation of PET data for cardiac PET/CT and PET/MR imaging.

BACKGROUND: Respiratory patient motion causes blurring of the PET images that may impact accurate quantification of perfusion and infarction extents in PET myocardial viability studies. In this study, we investigate the feasibility of correcting for respiratory motion directly in the PET-listmode data prior to image reconstruction using a data-driven, projection-based, respiratory motion compensation (DPR-MoCo) technique. METHODS: The DPR-MoCo method was validated using simulations of a XCAT phantom (Biograph mMR PET/MR) as well as experimental phantom acquisitions (Biograph mCT PET/CT). Seven patient studies following a dual-tracer (18F-FDG/13N-NH3) imaging-protocol using a PET/MR-system were also evaluated. The performance of the DPR-MoCo method was compared against reconstructions of the acquired data (No-MoCo), a reference gate method (gated) and an image-based MoCo method using the standard reconstruction-transform-average (RTA-MoCo) approach. The target-to-background ratio (TBRLV) in the myocardium and the noise in the liver (CoVliver) were evaluated for all acquisitions. For all patients, the clinical effect of the DPR-MoCo was assessed based on the end-systolic (ESV), the end-diastolic volumes (EDV) and the left ventricular ejection fraction (EF) which were compared to functional values obtained from the cardiac MR. RESULTS: The DPR-MoCo and the No-MoCo images presented with similar noise-properties (CoV) (P = .12), while the RTA-MoCo and reference-gate images showed increased noise levels (P = .05). TBRLV values increased for the motion limited reconstructions when compared to the No-MoCo reconstructions (P > .05). DPR-MoCo results showed higher correlation with the functional values obtained from the cardiac MR than the No-MoCo results, though non-significant (P > .05). CONCLUSION: The projection-based DPR-MoCo method helps to improve PET image quality of the myocardium without the need for external devices for motion tracking.

Assessment of attenuation correction for myocardial PET imaging using combined PET/MRI.

OBJECTIVE: To evaluate the frequency of artifacts in MR-based attenuation correction (AC) maps and their impact on the quantitative accuracy of PET-based flow and metabolism measurements in a cohort of consecutive heart failure patients undergoing combined PET/MR imaging. METHODS: Myocardial viability studies were performed in 20 patients following a dual-tracer protocol involving the assessment of myocardial perfusion (13N-NH3: 813 ± 86 MBq) and metabolism (18F-FDG: 335 ± 38 MBq). All acquisitions were performed using a fully-integrated PET/MR system, with standard DIXON-attenuation correction (DIXON-AC) mapping for each PET scan. All AC maps were examined for spatial misalignment with the emission data, total lung volume, susceptibility artifacts, and tissue inversion (TI). Misalignment and susceptibility artifacts were corrected using rigid co-registration and retrospective filling of the susceptibility-induced gaps, respectively. The effects of the AC artifacts were evaluated by relative difference measures and perceived changes in clinical interpretations. RESULTS: Average respiratory misalignment of (7 ± 4) mm of the PET-emission data and the AC maps was observed in 18 (90%) patients. Substantial changes in the lung volumes of the AC maps were observed in the test-retest analysis (ratio: 1.0 ± 0.2, range: 0.8-1.4). Susceptibility artifacts were observed in 10 (50%) patients, while six (30%) patients had TI artifacts. Average differences of 14 ± 10% were observed for PET images reconstructed with the artifactual AC maps. The combined artifact effects caused false-positive findings in three (15%) patients. CONCLUSION: Standard DIXON-AC maps must be examined carefully for artifacts and misalignment effects prior to AC correction of cardiac PET/MRI studies in order to avoid misinterpretation of biased perfusion and metabolism readings from the PET data.

Partial volume correction for improved PET quantification in 18F-NaF imaging of atherosclerotic plaques.

BACKGROUND: Accurate quantification of plaque imaging using 18F-NaF PET requires partial volume correction (PVC). METHODS: PVC of PET data was implemented by the use of a local projection (LP) method. LP-based PVC was evaluated with an image quality (NEMA) and with a thorax phantom with "plaque-type" lesions of 18-36 mL. The validated PVC method was then applied to a cohort of 17 patients, each with at least one plaque in the carotid or ascending aortic arteries. In total, 51 calcified (HU > 110) and 16 non-calcified plaque lesions (HU < 110) were analyzed. The lesion-to-background ratio (LBR) and the relative change of LBR (ΔLBR) were measured on PET. RESULTS: Following PVC, LBR of the spheres (NEMA phantom) was within 10% of the original values. LBR of the thoracic lesions increased by 155% to 440% when the LP-PVC method was applied to the PET images. In patients, PVC increased the LBR in both calcified [mean = 78% (-8% to 227%)] and non-calcified plaques [mean = 41%, (-9%-104%)]. CONCLUSIONS: PVC helps to improve LBR of plaque-type lesions in both phantom studies and clinical patients. Better results were obtained when the PVC method was applied to images reconstructed with point spread function modeling.

Tissue Oximetry as a Potential Alternative to Indocyanine Green (ICG) Perfusion Assessment in Colorectal Anastomotic Cases.

INTRODUCTION: Anastomotic margin tissue perfusion is recognized as critical to successful colorectal anastomosis creation. Near-infrared (NIR) fluorescence imaging with indocyanine green (ICG) is the most common modality used by surgeons as an adjunct to clinical assessment in confirming the adequacy of tissue perfusion. Tissue oxygenation as a surrogate for tissue perfusion has been described in a variety of surgical specialties but its use in colorectal surgery has been limited. Here, we report our experience using a handheld tissue-oxygen meter, IntraOx, for the evaluation of colorectal tissue bed oxygen saturation (StO 2 ) and compared its utility with NIR-ICG in identifying the viability of colonic tissue before anastomosis in a range of colorectal procedures. MATERIALS AND METHODS: This was an institutional review board-approved multicenter trial consisting of 100 patients undergoing elective colon resections. After specimen mobilization, a clinical margin was chosen based on the oncologic, anatomic, and clinical assessment as per the clinicians' standard technique. The IntraOx device was then used to take a baseline reading of colonic tissue oxygenation on a normal segment of perfused colon. Following this, measurements were taken circumferentially at 5 cm intervals along the bowel proximally and distally to the clinical margin. A StO 2 margin was then determined based on the point at which the StO 2 dropped off by ≥10 percentage points. This was then compared with the NIR-ICG margin using the Spy-Phi system. RESULTS: StO 2 was found to have a sensitivity and specificity of 94.8% and 93.1%, respectively, and a positive predictive value and negative predictive value of 93.5% and 94.5%, respectively when compared with NIR-ICG. At the 4-week follow-up, no significant complications or leaks were reported. CONCLUSIONS: The IntraOx handheld device was found to be similar to NIR-ICG in identifying a well-perfused margin of colonic tissue while having the added benefits of high portability and reduced costs. Further studies looking at the effect of the IntraOx on preventing colonic anastomotic complications such as leak and stricture are warranted.

Polymicrogyria: An Unusual Case of Secondary Mania.

BACKGROUND: Secondary mania refers to a manic episode that arises during a medical illness other than bipolar disorder or in response to a drug or medication. As the psychopathological features of secondary mania resemble those of mania due to bipolar disorder, misdiagnosis is frequent. PURPOSE AND BASIC PROCEDURES: We present the case of a 20-year-old woman who developed a manic episode with psychotic symptoms, in whom polymicrogyria, a malformation of the cortical development with abnormal electroencephalographic activity, was documented. After initiating antiepileptic management, the affective symptoms completely subsided. MAIN FINDINGS: To date, no specific recommendations are available concerning when to perform advanced studies in patients with a manic episode; however, as our case shows, these are much needed. PRINCIPAL CONCLUSION: Because the treatment of secondary conditions largely depends on finding the underlying cause, patients with a new-onset mania should undergo a thorough assessment for secondary causes.

Feasibility of dose reduction for [18F]FDG-PET/MR imaging of patients with non-lesional epilepsy.

The aim of the study was to evaluate the effect of reduced injected [18F]FDG activity levels on the quantitative and diagnostic accuracy of PET images of patients with non-lesional epilepsy (NLE).Nine healthy volunteers and nine patients with NLE underwent 60-min dynamic list-mode (LM) scans on a fully-integrated PET/MRI system. Injected FDG activity levels were reduced virtually by randomly removing counts from the last 10-min of the LM data, so as to simulate the following activity levels: 50 %, 35 %, 20 %, and 10 % of the original activity. Four image reconstructions were evaluated: standard OSEM, OSEM with resolution recovery (PSF), the A-MAP, and the Asymmetrical Bowsher (AsymBowsher) algorithms. For the A-MAP algorithms, two weights were selected (low and high). Image contrast and noise levels were evaluated for all subjects while the lesion-to-background ratio (L/B) was only evaluated for patients. Patient images were scored by a Nuclear Medicine physician on a 5-point scale to assess clinical impression associated with the various reconstruction algorithms.The image contrast and L/B ratio characterizing all four reconstruction algorithms were similar, except for reconstructions based on only 10 % of total counts. Based on clinical impression, images with diagnostic quality can be achieved with as low as 35 % of the standard injected activity. The selection of algorithms utilizing an anatomical prior did not provide a significant advantage for clinical readings, despite a small improvement in L/B (< 5 %) using the A-MAP and AsymBowsher reconstruction algorithms.In patients with NLE who are undergoing [18F]FDG-PET/MR imaging, the injected [18F]FDG activity can be reduced to 35 % of the original dose levels without compromising.

A copper(ii) peptide helicate selectively cleaves DNA replication foci in mammalian cells.

The use of copper-based artificial nucleases as potential anticancer agents has been hampered by their poor selectivity in the oxidative DNA cleavage process. An alternative strategy to solve this problem is to design systems capable of selectively damaging noncanonical DNA structures that play crucial roles in the cell cycle. We designed an oligocationic CuII peptide helicate that selectively binds and cleaves DNA three-way junctions (3WJs) and induces oxidative DNA damage via a ROS-mediated pathway both in vitro and in cellulo, specifically at DNA replication foci of the cell nucleus, where this DNA structure is transiently generated. To our knowledge, this is the first example of a targeted chemical nuclease that can discriminate with high selectivity 3WJs from other forms of DNA both in vitro and in mammalian cells. Since the DNA replication process is deregulated in cancer cells, this approach may pave the way for the development of a new class of anticancer agents based on copper-based artificial nucleases.

Technical note: A PET/MR coil with an integrated, orbiting 511 keV transmission source for PET/MR imaging validated in an animal study.

BACKGROUND: MR-based methods for attenuation correction (AC) in PET/MRI either neglect attenuation of bone, or use MR-signal derived information about bone, which leads to a bias in quantification of tracer uptake in PET. In a previous study, we presented a PET/MRI specific MR coil with an integrated transmission source (TX) system allowing for direct measurement of attenuation. In phantom measurements, this system successfully reproduced the linear attenuation coefficient of water. PURPOSE: The purpose of this study is to validate the TX system in a clinical setting using animals and to show its applicability compared to standard clinical methods. METHODS: As test subject, a 15-kg piglet was injected with 53 MBq of 18F-NaF. The µ-map obtained with the TX system and the reconstructed activity distribution were compared to four established AC methods: a Dixon sequence, an ultra-short echo time (UTE) sequence, a CT scan, and a 511 keV transmission scan using a Siemens ECAT EXACT HR+ as the reference. The PET/MRI measurements were performed on a Siemens Biograph mMR to obtain the µ-map using the TX system as well as the Dixon and UTE sequence directly followed by the CT and ECAT measurements. RESULTS: The reconstructed activity distribution using the TX system for AC showed similar results compared to the reference (<5% difference in hot regions) and outperformed the MR-based methods as implemented in the PET/MRI system (<10% difference in hot regions). However, the additional hardware of the TX system adds complexity to the acquisition process. CONCLUSION: Our porcine study demonstrates the feasibility of post-injection transmission scans using the developed TX system in a clinical setting. This makes it a useful tool for PET/MRI in cases where transmission information is needed for AC. Potential applications are studies using larger animals where state-of-the-art atlas-based or artificial intelligence AC methods are not available.

Selective recognition of A/T-rich DNA 3-way junctions with a three-fold symmetric tripeptide.

Non-canonical DNA structures, particularly 3-Way Junctions (3WJs) that are transiently formed during DNA replication, have recently emerged as promising chemotherapeutic targets. Here, we describe a new approach to target 3WJs that relies on the cooperative and sequence-selective recognition of A/T-rich duplex DNA branches by three AT-Hook peptides attached to a three-fold symmetric and fluorogenic 1,3,5-tristyrylbenzene core.

Implementation of a Spatially-Variant and Tissue-Dependent Positron Range Correction for PET/CT Imaging.

Aim: To develop and evaluate a new approach for spatially variant and tissue-dependent positron range (PR) correction (PRC) during the iterative PET image reconstruction. Materials and Methods: The PR distributions of three radionuclides (18F, 68Ga, and 124I) were simulated using the GATE (GEANT4) framework in different material compositions (lung, water, and bone). For every radionuclide, the uniform PR kernel was created by mapping the simulated 3D PR point cloud to a 3D matrix with its size defined by the maximum PR in lung (18F) or water (68Ga and 124I) and the PET voxel size. The spatially variant kernels were composed from the uniform PR kernels by analyzing the material composition of the surrounding medium for each voxel before implementation as tissue-dependent, point-spread functions into the iterative image reconstruction. The proposed PRC method was evaluated using the NEMA image quality phantom (18F, 68Ga, and 124I); two unique PR phantoms were scanned and evaluated following OSEM reconstruction with and without PRC using different metrics, such as contrast recovery, contrast-to-noise ratio, image noise and the resolution evaluated in terms of full width at half maximum (FWHM). Results: The effect of PRC on 18F-imaging was negligible. In contrast, PRC improved image contrast for the 10-mm sphere of the NEMA image quality phantom filled with 68Ga and 124I by 33 and 24%, respectively. While the effect of PRC was less noticeable for the larger spheres, contrast recovery still improved by 5%. The spatial resolution was improved by 26% for 124I (FWHM of 4.9 vs. 3.7 mm). Conclusion: For high energy positron-emitting radionuclides, the proposed PRC method helped recover image contrast with reduced noise levels and with improved spatial resolution. As such, the PRC approach proposed here can help improve the quality of PET data in clinical practice and research.