[Crossed views on depressive symptomatology with suicidal expression in the elderly]. / Regards croisés sur la symptomatologie dépressive à expression suicidaire du sujet âgé.

Presentation of the clinical situation of Mrs. M. The mobile psychiatric team of the Marchant hospital in Toulouse (31) is requested by the coordinating physician of an establishment for dependent elderly people for an evaluation of the mood with suicidal risk in this 92 year old patient who has recently entered the structure.

Striatal and cerebellar vesicular acetylcholine transporter expression is disrupted in human DYT1 dystonia.

Early-onset torsion dystonia (TOR1A/DYT1) is a devastating hereditary motor disorder whose pathophysiology remains unclear. Studies in transgenic mice suggested abnormal cholinergic transmission in the putamen, but this has not yet been demonstrated in humans. The role of the cerebellum in the pathophysiology of the disease has also been highlighted but the involvement of the intrinsic cerebellar cholinergic system is unknown. In this study, cholinergic neurons were imaged using PET with 18F-fluoroethoxybenzovesamicol, a radioligand of the vesicular acetylcholine transporter (VAChT). Here, we found an age-related decrease in VAChT expression in the posterior putamen and caudate nucleus of DYT1 patients versus matched controls, with low expression in young but not in older patients. In the cerebellar vermis, VAChT expression was also significantly decreased in patients versus controls, but independently of age. Functional connectivity within the motor network studied in MRI and the interregional correlation of VAChT expression studied in PET were also altered in patients. These results show that the cholinergic system is disrupted in the brain of DYT1 patients and is modulated over time through plasticity or compensatory mechanisms.

Brain 5-HT1A Receptor Binding in Multiple System Atrophy: An [18 F]-MPPF PET Study.

BACKGROUND: Loss of medullary serotonin (5-hydroxytryptamine) neurons has been linked to respiratory disturbances in multiple system atrophy (MSA). Broader 5-hydroxytryptamine dysfunction may contribute to additional motor/nonmotor symptoms in MSA. The objective of this study was to compare brain 5-hydroxytryptamine1A receptor binding between MSA and healthy controls. Secondary objectives were to compare 5-hydroxytryptamine1A receptor binding between MSA and Parkinson's disease (PD) and to assess potential associations with motor/nonmotor symptoms in MSA. METHODS: 2'-Methoxyphenyl-(N-2'-pyridinyl)-p-18F-fluoro-benzamidoethylpiperazine positron emission tomography was performed in matched MSA patients (n = 16), PD patients (n = 15), and healthy controls (n = 18). RESULTS: 2'-Methoxyphenyl-(N-2'-pyridinyl)-p-18F-fluoro-benzamidoethylpiperazine distribution volume ratios were lower in MSA patients versus healthy controls in several brain regions including the caudate, raphe nuclei, thalamus, and brain stem. Distribution volume ratios were also lower in brain stem and amygdala in MSA versus PD. Moderate associations were found between 2'-methoxyphenyl-(N-2'-pyridinyl)-p-18F-fluoro-benzamidoethylpiperazine distribution volume ratios and fatigue, pain, and apathy in MSA. CONCLUSION: Our results demonstrate 5-hydroxytryptamine dysfunction in several brain regions in MSA, which may contribute to fatigue, pain, and apathy. © 2020 International Parkinson and Movement Disorder Society.

Silicon-Containing Neurotensin Analogues as Radiopharmaceuticals for NTS1-Positive Tumors Imaging.

Several independent studies have demonstrated the overexpression of NTS1 in various malignancies, which make this receptor of interest for imaging and therapy. To date, radiolabeled neurotensin analogues suffer from low plasmatic stability and thus insufficient availability for high uptake in tumors. We report the development of 68Ga-radiolabeled neurotensin analogues with improved radiopharmaceutical properties through the introduction of the silicon-containing amino acid trimethylsilylalanine (TMSAla). Among the series of novel radiolabeled neurotensin analogues, [68Ga]Ga-JMV6659 exhibits high hydrophilicity (log D7.4 = -3.41 ± 0.14), affinity in the low nanomolar range toward NTS1 (Kd = 6.29 ± 1.37 nM), good selectivity (Kd NTS1/Kd NTS2 = 35.9), and high NTS1-mediated internalization. It has lower efflux and prolonged plasmatic half-life in human plasma as compared to the reference compound ([68Ga]Ga-JMV6661 bearing the minimum active fragment of neurotensin and the same linker and chelate as other analogues). In nude mice bearing HT-29 xenograft, [68Ga]Ga-JMV6659 uptake reached 7.8 ± 0.54 %ID/g 2 h post injection. Uptake was decreased to 1.38 ± 0.71 %ID/g with injection of excess of non-radioactive neurotensin. Radiation dose as extrapolated to human was estimated as 2.35 ± 0.6 mSv for a standard injected activity of 100MBq. [68Ga]Ga-JMV6659 was identified as a promising lead compound suitable for PET imaging of NTS1-expressing tumors.

Neurotensin Receptor-1 Expression in Human Prostate Cancer: A Pilot Study on Primary Tumors and Lymph Node Metastases.

Neurotensin and its high-affinity receptor, NTR1, are involved in the growth of various tumors. Few data are available regarding NTR1 expression in normal and tumoral human prostate tissue samples. NTR1 expression was assessed using immunohistochemistry in 12 normal prostate tissues, 11 benign prostatic hyperplasia (BPH), 44 prostate cancers, and 15 related metastatic lymph nodes (one per patient, when available). NTR1-staining was negative in normal prostate and BPH samples. NTR1 was overexpressed in four out of 44 (9.1%) primary tumors. There was no clear association between NTR1 overexpression and age, PSA-values, Gleason score, pT-status, nodal-status, or margin. NTR1 was expressed at a high level of five out of 15 (33.3%) metastatic lymph nodes. NTR1 overexpression was thus more frequent in metastatic lymph nodes than in primary tumors (p = 0.038). In this limited series of samples, NTR1 overexpression was observed in few primary prostate cancers. Upregulation was more frequent in related lymph nodes. The presence of this target in metastatic lymph nodes may open new perspectives for imaging and radionuclide therapy of prostate cancer. Factors driving NTR1 expression in primary prostate cancer and in nodal and distant metastases still need to be characterized.

Evidence of Neanderthals in the Balkans: The infant radius from Kozarnika Cave (Bulgaria).

Excavations conducted by a Bulgarian-French team at Kozarnika Cave (Balkans, Bulgaria) during several seasons yielded a long Paleolithic archaeological sequence and led to the discovery of important faunal, lithic, and human samples. This paper aims to describe the unpublished radius shaft of an infant who died approximately before the sixth month postnatal that was recovered from layer 10b, which contained East Balkan Levallois Mousterian with bifacial leaf points. The layer was dated between 130 and 200 ka (large mammals biochronology) and between 128 ± 13 ka and 183 ± 14 ka (OSL), i.e. OIS6. Here we show that, given the scarcity of Middle Pleistocene infant remains in general, and Middle Paleolithic human remains from this part of Eastern Europe in particular, the study of the Kozarnika specimen is of special interest. We discuss its place in the Middle Pleistocene European hominine record and substantiate the hypothesis of early Neanderthal presence in the eastern Balkans.

[Geriatric psychiatry and dementia]. / Gérontopsychiatrie et démence.

Behavioural disorders linked to dementia are common. The intertwining of psychiatric and neurodegenerative pathologies means caregivers are faced with complex situations on a daily basis. The expertise of the geriatric psychiatry teams helps to guide the clinical reasoning and to find the best nursing approach in order to understand the symptom and support the patient.

Evaluation of (68)Ga-DOTA-TOC PET/CT for the detection of duodenopancreatic neuroendocrine tumors in patients with MEN1.

CONTEXT: Somatostatin receptor scintigraphy with (111)In-pentetreotide (SRS) is used to detect duodenopancreatic neuroendocrine tumors (dpNETs) in multiple endocrine neoplasia type 1 (MEN1). However, SRS has limited sensitivity for this purpose. Positron emission tomography/computed tomography (PET/CT) with (68)Ga-DOTA-TOC has a higher rate of sporadic dpNETs detection than SRS but there is little data for dpNETs detection in MEN1. PURPOSE: To compare the performances of (68)Ga-DOTA-TOC PET/CT, SRS and contrast-enhanced computed tomography (CE-CT) to diagnose dpNETs in MEN1. DESIGN AND SETTING: Single-institution prospective comparative study PATIENTS AND METHODS: Nineteen consecutive MEN1 patients (aged 47 ± 13 years) underwent (68)Ga-DOTA-TOC PET/CT, SRS, and CE-CT within 2 months in random order. Blinded readings of images were performed separately by experienced physicians. Unblinded analysis of CE-CT, combined with additional magnetic resonance imaging, endoscopic-ultrasound, (18)F-2-fluoro-deoxy-D-glucose ((18)F-FDG) PET/CT or histopathology results served as reference standard for dpNETs diagnosis. RESULTS: The sensitivity of (68)Ga-DOTA-TOC PET/CT, SRS, and CE-CT was 76, 20, and 60 %, respectively (p < 0.0001). All the true-positive lesions detected by SRS were also depicted on (68)Ga-DOTA-TOC PET/CT. (68)Ga-DOTA-TOC PET/CT detected lesions of smaller size than SRS (10.7 ± 7.6 and 15.2 ± 5.9 mm, respectively, p < 0.03). False negatives of (68)Ga-DOTA-TOC PET/CT included small dpNETs (<10 mm) and (18)F-FDG PET/CT positive aggressive dpNETs. No false positives were recorded. In addition, whole-body mapping with (68)Ga-DOTA-TOC PET/CT identified extra-abdominal MEN1-related tumors including one neuroendocrine thymic carcinoma identified by the three imaging procedures, one bronchial carcinoid undetected by CE-CT and three meningiomas undetected by SRS. CONCLUSIONS: Owing to higher diagnostic performance, (68)Ga-DOTA-TOC PET/CT (or alternative (68)Ga-labeled somatostatin analogues) should replace (111)In-pentetreotide in the investigation of MEN1 patients.

Comparative effectiveness of [(18) F]-fluorocholine PET-CT and pelvic MRI with diffusion-weighted imaging for staging in patients with high-risk prostate cancer.

BACKGROUND: Accurate staging is important before surgical decision in patients with high-risk prostate cancer (PCa). The purpose of this study was to prospectively compare the diagnostic performance of (18) F-FCholine and MRI with diffusion weighted imaging (DWIMRI) for local and regional lymph node (LN) staging before radical prostatectomy (RP) with extended pelvic lymphadenectomy (PLND). METHODS: We identified 47 patients who underwent (18) F-FCholine and DWIMRI followed by surgical treatment (either prostatectomy or LN dissection or an association of prostatectomy and LN dissection) between May 2010 and December 2012 at Bordeaux University Hospital. These patients were part of a prospective study (EudraCT number 2009-014839-21) evaluating the interest of (18) F-FCholine in staging of high-risk PCa. Diagnostic performances were retrospectively determined for each of (18) F-FCholine and DWIMRI considering LN invasion, each of prostate sextants, capsular invasion and extension to seminal vesicles. (18) F-FCholine and MR findings were correlated with histological findings. RESULTS: In a region-based LN analysis, the sensitivity and positive predictive value specificity were respectively, 56% and 98% for (18) F-Choline, and 17% and 97% for DWIMRI. In a patient-based analysis the sensitivity and positive predictive value were respectively 78% and 94% for (18) F-Choline and 33% and 84% for DWIMRI (P = 0.015). For tumor staging, DWIMRI showed better performances with a better specificity (69%) for sextants analysis and sensitivity to detect seminal vesicle invasion (73% vs. 36%). CONCLUSIONS: (18) F-FCholine imaging appears to provide helpful additional information in the staging of high-risk PCa. It appears essential for predicting LN status due to its higher sensitivity and specificity for LN involvement. However, despite excellent performance, it cannot replace MRI that remains better for tumoral localization and local evaluation, especially for seminal vesicle invasion. PATIENT SUMMARY: This study highlights the interest of (18) F-Choline in the staging of high risk prostate cancer in addition with DWI MRI, especially so in the evaluation of lymph node involvement due to its high sensitivity and excellent specificity.

Improvement of in vivo quantification of [123I]-Iodobenzovesamicol in single-photon emission computed tomography/computed tomography using anatomic image to brain atlas nonrigid registration.

Brain anatomy variability is a major problem in quantifying functional images in nuclear medicine, in particular relative to aging and neurodegenerative diseases. The aim of this study was to compare affine and elastic model-based methods for magnetic resonance imaging (MRI) to brain atlas registration and to assess their impact on the quantification of cholinergic neurotransmission. Patients with multiple system atrophy (MSA) and age-matched healthy subjects underwent an MRI and a single-photon emission computed tomographic (SPECT) examination using [123I]-iodobenzovesamicol (IBVM). Both affine and elastic methods were compared to register the subjects' MRI with the Montreal Neurological Institute brain atlas. Performance of the registration accuracy was quantitatively assessed and the impact on the IBVM quantification was studied. For both subject groups, elastic registration achieved better quantitative performance compared to the affine model. For patients suffering from neurogenerative disease, this study demonstrates the importance and relevance of MRI to atlas registration in quantification of neuronal integrity. In this context, in comparison with rigid registrations, an elastic model-based registration provides the best relocation of the brain structures to the atlas for accurately quantifying cholinergic neurotransmission.

Quantification of Hypoxia in Human Glioblastoma using PET with 18F-FMISO.

PURPOSE: This study aimed to investigate the results of compartmental modeling (CM) and spectral analysis (SA) generated with dynamic 18F-FMISO tumor images. Besides, the regular tissue-to-blood ratio (TBR) images were derived and compared with the dynamic models. METHODS: Nine subjects with glioblastoma underwent PET/CT imaging with the 18F-FMISO tracer. The protocol for PET imaging began with 15 min in dynamic mode and two 10-min duration static images at 120 min and 180 min post-injection. We used the two-tissue compartmental model for CM at the voxel basis, and we conducted SA to estimate the 18F-FMISO accumulation within each voxel. We also investigated the usual tumor-to-blood ratio (TBR) for comparison. RESULTS: The images of the tumor showed different patterns of hypoxia and necrosis as a function of PET scanning times, while CM and SA methods based on dynamic PET imaging equally located tumor hypoxia. The mean correlation of Ki images of all subjects between CM and SA was 0.63 ± 0.19 (0.24-0.86). CM produced less noisy K i images than SA, and, in the contrary, SA produced accumulation component images more clear than with CM. CM-K i and SA-K i images were correlated with TBR images (r = 0.72 ± 0.20 and 0.56 ± 0.26, respectively). In the only subject having a continuously increasing tumor time-activity curve, the k 3 image showed a high uptake in the necrosis region which was not apparent in TBR or K i images. CONCLUSION: Based on these results, the combination of CM and SA approaches was found more appropriate in generating voxel-based hypoxia images.

Early Middle Stone Age personal ornaments from Bizmoune Cave, Essaouira, Morocco.

Ornaments such as beads are among the earliest signs of symbolic behavior among human ancestors. Their appearance signals important developments in both cognition and social relations. This paper describes and presents contextual information for 33 shell beads from Bizmoune Cave (southwest Morocco). Many of the beads come as deposits dating to ≥142 thousand years, making them the oldest shell beads yet recovered. They extend the dates for the first appearance of this behavior into the late Middle Pleistocene. The ages and ubiquity of beads in Middle Stone Age (MSA) sites in North Africa provide further evidence of the potential importance of these artifacts as signals of identity. The early and continued use of Tritia gibbosula and other material culture traits also suggest a remarkable degree of cultural continuity among early MSA Homo sapiens groups across North Africa.

Changes Over Time of Diffusion MRI in the White Matter of Aging Brain, a Good Predictor of Verbal Recall.

Objective: Extensive research using water-diffusion MRI reported age-related modifications of cerebral White Matter (WM). Moreover, water-diffusion parameter modifications have been frequently associated with cognitive performances in the elderly sample, reinforcing the idea of aging inducing microstructural disconnection of the brain which in turn impacts cognition. However, only few studies really assessed over-time modifications of these parameters and their relationship with episodic memory outcome of elderly. Materials and Methods: One-hundred and thirty elderly subjects without dementia (74.1 ± 4.1 years; 47% female) were included in this study. Diffusion tensor imaging (DTI) was performed at two-time points (3.49 ± 0.68 years apart), allowing the assessment of changes in water-diffusion parameters over time using a specific longitudinal pipeline. White matter hyperintensity (WMH) burden and gray matter (GM) atrophy were also measured on FLAIR and T1-weighted sequences collected during these two MRI sessions. Free and cued verbal recall scores assessed at the last follow-up of the cohort were used as episodic memory outcome. Changes in water-diffusion parameters over time were included in serial linear regression models to predict retrieval or storage ability of elderly. Results: GM atrophy and an increase in mean diffusivity (MD) and WMH load between the two-time points were observed. The increase in MD was significantly correlated with WMH load and the different memory scores. In models accounting for the baseline cognitive score, GM atrophy, or WMH load, MD changes still significantly predict free verbal recall, and not total verbal recall, suggesting the specific association with the retrieval deficit in healthy aging. Conclusion: In elderly, microstructural WM changes are good predictors of lower free verbal recall performances. Moreover, this contribution is not only driven by WMH load increase. This last observation is in line with studies reporting early water-diffusion modification in WM tissue during aging, resulting lately in the appearance of WMH on conventional MRI.

Design, synthesis, and biological evaluation of a multifunctional neuropeptide-Y conjugate for selective nuclear delivery of radiolanthanides.

BACKGROUND: Targeting G protein-coupled receptors on the surface of cancer cells with peptide ligands is a promising concept for the selective tumor delivery of therapeutically active cargos, including radiometals for targeted radionuclide therapy (TRT). Recently, the radiolanthanide terbium-161 (161Tb) gained significant interest for TRT application, since it decays with medium-energy ß-radiation but also emits a significant amount of conversion and Auger electrons with short tissue penetration range. The therapeutic efficiency of radiometals emitting Auger electrons, like 161Tb, can therefore be highly boosted by an additional subcellular delivery into the nucleus, in order to facilitate maximum dose deposition to the DNA. In this study, we describe the design of a multifunctional, radiolabeled neuropeptide-Y (NPY) conjugate, to address radiolanthanides to the nucleus of cells naturally overexpressing the human Y1 receptor (hY1R). By using solid-phase peptide synthesis, the hY1R-preferring [F7,P34]-NPY was modified with a fatty acid, a cathepsin B-cleavable linker, followed by a nuclear localization sequence (NLS), and a DOTA chelator (compound pb12). In this proof-of-concept study, labeling was performed with either native terbium-159 (natTb), as surrogate for 161Tb, or with indium-111 (111In). RESULTS: [natTb]Tb-pb12 showed a preserved high binding affinity to endogenous hY1R on MCF-7 cells and was able to induce receptor activation and internalization similar to the hY1R-preferring [F7,P34]-NPY. Specific internalization of the 111In-labeled conjugate into MCF-7 cells was observed, and importantly, time-dependent nuclear uptake of 111In was demonstrated. Study of metabolic stability showed that the peptide is insufficiently stable in human plasma. This was confirmed by injection of [111In]In-pb12 in nude mice bearing MCF-7 xenograft which showed specific uptake only at very early time point. CONCLUSION: The multifunctional NPY conjugate with a releasable DOTA-NLS unit represents a promising concept for enhanced TRT with Auger electron-emitting radiolanthanides. Our research is now focusing on improving the reported concept with respect to the poor plasmatic stability of this promising radiopeptide.

Analysis of hypoxia in human glioblastoma tumors with dynamic 18F-FMISO PET imaging.

Gliomas are the most common type of primary brain tumors and are classified as grade IV. Necrosis and hypoxia are essential diagnostic features which result in poor prognosis of gliomas. The aim of this study was to report quantitative temporal analyses aiming at determining the hypoxic regions in glioblastoma multiforme and to suggest an optimal time for the clinical single scan of hypoxia. Nine subjects were imaged with PET and 18F-FMISO in dynamic mode for 15 min followed with static scans at 2, 3 and 4 h post-injection. Spectral analysis, tumor-to-blood ratio (TBR) and tumor-to-normal tissue ratio (TNR) were used to delimit perfused and hypoxic tumor regions. TBR and TNR images were further scaled by thresholding at 1.2, 1.4, 2 and 2.5 levels. The images showed a varying tumor volume with time. TBR produced broader images of the tumor than TNR considering the same thresholds on intensity. Spectral analysis reliably determined hypoxia with different degrees of perfusion. By comparing TBR and TNR with spectral analysis images, weak to moderate correlation coefficients were found for most thresholding values and imaging times (range: 0 to 0.69). Hypoxic volume (HV) estimated from the net uptake rate (Ki) were changing among imaging times. The minimum HV changes were found between 3 h and 4 h, confirming that after 3 h, there was a very low exchange of 81F-FMISO between blood and tumor. On the other hand, hypoxia started to dominate the perfused tissue at 90 min, suggesting this time is suitable for a single scan acquisition irrespective of tumor status being highly hypoxic or perfused. At this time, TBR and TNR were respectively found in the nine subjects as 1.72 ± 0.22 and 1.74 ± 0.19.

Imaging of hypoxia in human glioblastoma with dynamic 18F-fluoromisonidazole PET.

Aim: The purpose of this study was to locate the levels of hypoxia in glioblastoma PET images measured with 18F-fluoromisonidazole in human subjects. It is recognized that tumors with hypoxia are resistant to treatment by radiotherapy and chemotherapy. Methods: The images were acquired in dynamic mode for 15 min or 30 min and in static mode for two single scans at 2 h and 3 h to allow the accumulation of the radiotracer in the tumor. The images were analyzed at the voxel basis with compartmental analysis (CA) and with the usual tumor-to-blood uptake ratio (TBR). Kmeans algorithm was applied to cluster the levels of hypoxia in the images. Results: TBR at a threshold of 1.2 at imaging times of 15 min, 2 h and 3 h produced images with different clusters. Also, the comparison of TBR with the distribution volume obtained with CA had a similarity index of 0.61 ± 0.05. Conclusion: We found some differences in defining the hypoxic volume within a tumor using TBR. The compartmental analysis allowed discrimination of the tumor hypoxic sub-volumes which can be useful for a better treatment with radiotherapy.

Comparison of the binding of the gastrin-releasing peptide receptor (GRP-R) antagonist 68Ga-RM2 and 18F-FDG in breast cancer samples.

The Gastrin-Releasing Peptide Receptor (GRPR) is over-expressed in estrogen receptor (ER) positive breast tumors and related metastatic lymph nodes offering the opportunity of imaging and therapy of luminal tumors. 68Ga-RM2 binding and 18F-FDG binding in tumoral zones were measured and compared using tissue micro-imaging with a beta imager on 14 breast cancer samples (10 primaries and 4 associated metastatic lymph nodes). Results were then assessed against ER expression, progesterone receptor (PR) expression, HER2 over-expression or not and Ki-67 expression. GRPR immunohistochemistry (IHC) was also performed on all samples. We also retrospectively compared 68Ga-RM2 and 18F-FDG bindings to 18F-FDG SUVmax on the pre-therapeutic PET/CT examination, if available. 68Ga-RM2 binding was significantly higher in tumors expressing GRPR on IHC than in GRPR-negative tumors (P = 0.022). In ER+ tumors, binding of 68Ga-RM2 was significantly higher than 18F-FDG (P = 0.015). In tumors with low Ki-67, 68Ga-RM2 binding was also significantly increased compared to 18F-FDG (P = 0.029). Overall, the binding of 68Ga-RM2 and 18F-FDG displayed an opposite pattern in tumor samples and 68Ga-RM2 binding was significantly higher in tumors that had low 18F-FDG binding (P = 0.021). This inverse correlation was also documented in the few patients in whom a 18F-FDG PET/CT examination before surgery was available. Findings from this in vitro study suggest that GRPR targeting can be an alternative to 18F-FDG imaging in ER+ breast tumors. Moreover, because GRPR antagonists can also be labeled with lutetium-177 this opens new avenues for targeted radionuclide therapy in the subset of patients with progressive metastatic disease following conventional treatments.

68Ga-PSMA-617 Compared With 68Ga-RM2 and 18F-FCholine PET/CT for the Initial Staging of High-Risk Prostate Cancer.

Ga-labeled prostate-specific membrane antigen inhibitors and Ga-labeled gastrin-releasing peptide receptor antagonists showed interesting results for staging biochemically recurrent prostate cancer. In this case, Ga-prostate-specific membrane antigen-617 PET/CT, Ga-RM2 PET/CT, and F-choline PET/CT were performed in a patient (66-year-old man, prostate-specific antigen = 6.7 ng/mL) with biopsy-proven Gleason 9 (5 + 4) prostate cancer, candidate for radical prostatectomy and lymph node dissection.