Evaluation of novel anti-CEACAM6 antibody-based conjugates for radioimmunotheranostics of pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant solid tumor that lacks early diagnostic methods. Recently, targeted immunotherapy and radiotherapy have been integrated with radionuclide-antibody conjugate drugs, which can be used for targeted diagnosis and dynamic imaging of tumors. CEACAM6 is overexpressed in pancreatic tumors and is a potential theranostic target for PDAC. We aimed to develop a novel targeted carrier for theranostics of PDAC and other solid tumors. METHODS: Based on camelid heavy-chain-only antibodies, we developed a CEACAM6-targeting recombinant antibody NY004, and evaluated it as a novel antibody-carrier for imaging and therapy of cancer in tumor models. We labeled NY004 with theranostic nuclides and applied this self-developed antibody platform in diagnostic imaging and antitumor assessment in PDAC models. RESULTS: Through microPET, IHC, and biodistribution assays, targeting and biodistribution of [89Zr]-NY004 in solid tumors including PDAC was examined, and the investigated tumors were all CEACAM6-positive malignancies. We found that NY004 was suitable for use as a drug carrier for radioimmunotheranostics. Our study showed that NY004 was characterized by high targeted uptake and a long retention time in PANC-1 tumors (up to 6 days post-injection), with good specificity and high imaging efficiency. Therapeutic evaluation of the radionuclide-labeled antibody drug [177Lu]-NY004 in PDAC tumor-bearing model revealed that NY004 had high and prolonged uptake in tumors, relatively low non-target organ uptake, and good anti-tumor efficacy. CONCLUSION: As a drug platform for radiotheranostics, CEACAM6-specific antibody NY004 met the requirements of easy-labeling, targeting specificity, and effective persistence in pancreatic adenocarcinoma tissues. KEY POINTS: • [89Zr]-NY004 has good specificity and high imaging efficiency, and is characterized by high tumor-targeting uptake and a long tumor retention time as a PET molecular imaging tracer. • Therapeutic radionuclide-conjugated antibody drug [177Lu]-NY004 has high uptake and prolonged uptake duration in tumors, low non-target organ uptake, and significant tumor-inhibiting efficacy in PDAC model. • The self-developed antibody structure NY004 is a promising drug platform for radioimmunotheranostics of CEACAM6-positive tumors including pancreatic ductal adenocarcinoma.

Positive rate and quantification of amyloid pathology with [18F]florbetapir in the urban Chinese population.

OBJECTIVES: Amyloid deposition is considered the initial pathology in Alzheimer's disease (AD). Personalized management requires investigation of amyloid pathology and the risk factors for both amyloid pathology and cognitive decline in the Chinese population. We aimed to investigate amyloid positivity and deposition in AD patients, as well as factors related to amyloid pathology in Chinese cities. METHODS: This cross-sectional multicenter study was conducted in Shanghai and Zhengzhou, China. All participants were recruited from urban communities and memory clinics. Amyloid positivity and deposition were analyzed based on amyloid positron emission tomography (PET). We used partial least squares (PLS) models to investigate how related factors contributed to amyloid deposition and cognitive decline. RESULTS: In total, 1026 participants were included: 768 participants from the community-based cohort (COMC) and 258 participants from the clinic-based cohort (CLIC). The overall amyloid-positive rates in individuals with clinically diagnosed AD, mild cognitive impairment (MCI), and normal cognition (NC) were 85.8%, 44.5%, and 26.9%, respectively. The global amyloid deposition standardized uptake value ratios (SUVr) (reference: cerebellar crus) were 1.44 ± 0.24, 1.30 ± 0.22, and 1.24 ± 0.14, respectively. CLIC status, apolipoprotein E (ApoE) ε4, and older age were strongly associated with amyloid pathology by PLS modeling. CONCLUSION: The overall amyloid-positive rates accompanying AD, MCI, and NC in the Chinese population were similar to those in published cohorts of other populations. ApoE ε4 and CLIC status were risk factors for amyloid pathology across the AD continuum. Education was a risk factor for amyloid pathology in MCI. Female sex and age were risk factors for amyloid pathology in NC. CLINICAL RELEVANCE STATEMENT: This study provides new details about amyloid pathology in the Chinese population. Factors related to amyloid deposition and cognitive decline can help to assess patients' AD risk. KEY POINTS: • We studied amyloid pathology and related risk factors in the Chinese population. •·The overall amyloid-positive rates in individuals with clinically diagnosed AD, MCI, and NC were 85.8%, 44.5%, and 26.9%, respectively. • These overall amyloid-positive rates were in close agreement with the corresponding prevalence for other populations.

Brain glucose metabolism and dopamine transporter changes in rats with morphine-induced conditioned place preference.

Addiction to morphine is a chronic brain disease leading to compulsive abuse. Drug addiction animal models with and without conditioned place preference (CPP) training have been used to investigate cue-elicited drug craving. We used 18 F-fluorodeoxyglucose (18 F-FDG) and 11 C-2-ß-carbomethoxy-3-ß-(4-fluorophenyl)tropane (11 C-CFT) micro-PET/CT scans to examine the regional changes in brain glucose metabolism and dopamine transporter (DAT) availability to study their relationship underlying drug memory in morphine-treated rat models with and without CPP. Standardized uptake value ratio (SUVr) of 18 F-FDG significantly decreased in the medial prefrontal cortex (mPFC) and cingulate with short-term morphine administration compared with the baseline condition. Voxelwise analysis indicated glucose metabolism alterations in the somatosensory cortex, hippocampus and cingulate in morphine-treated rats and in the striatum, thalamus, medial prefrontal cortex, primary motor cortex and many regions in the cortex in the CPP group compared with the baseline condition. Alterative glucose metabolism was also observed in the striatum, primary somatosensory cortex and some cortical regions in the CPP group compared with morphine alone group. DAT expression alterations were only observed in the long-term morphine compared with the short-term morphine group. This study shows that cerebral glucose metabolism significantly altered during morphine administration and CPP process mainly in the mPFC, striatum and hippocampus, which indicates that the function of these brain regions is involved in cue-induced craving and memory retrieval.

Comparison of [68 Ga]Ga-FAPI-04 and [18F]-FDG for the detection of primary and metastatic lesions in patients with gastric cancer: a bicentric retrospective study.

INTRODUCTION: The low sensitivity of [18F]-fluorodeoxyglucose ([18F]-FDG) for the diagnosis of gastric cancer limits its application. In this study, we aimed to investigate the potential advantage of [68 Ga]Ga-FAPI-04 over [18F]-FDG in the evaluation of gastric cancer. METHODS: This was a bicentric retrospective analysis of a prospective parent study (clinical trial: HS-KY-2020-826 (Huashan Hospital) and DF-2020-102 (Shanghai East Hospital)). Thirty-eight patients with gastric cancer (31 with adenocarcinoma and 7 with signet ring cell carcinoma) were included in this study. All of the participants underwent [68 Ga]Ga-FAPI-04 and [18F]-FDG imaging by positron emission tomography (PET)/computed tomography (CT) or PET/magnetic resonance (MR). The scans were interpreted by two experienced nuclear medicine physicians, and the maximum standardized uptake value (SUVmax) was calculated. Histopathological findings obtained from biopsy or resected surgical specimens were used as a reference for the final diagnosis. RESULTS: For the detection of primary gastric cancer, the sensitivities of [68 Ga]Ga-FAPI-04 PET and [18F]-FDG PET were 100% (38/38) and 82% (31/38), respectively (P = 0.016). Four cases of adenocarcinoma and three cases of signet ring cell carcinoma were missed by [18F]-FDG PET. The mean SUVmax of [68 Ga]Ga-FAPI-04 in tumours greater than 4 cm (11.0 ± 4.5) was higher than that in tumours less than 4 cm (4.5 ± 3.2) (P = 0.0015). The mean SUVmax of [68 Ga]Ga-FAPI-04 was higher in T2-4 tumours (9.7 ± 4.4) than in T1 tumours (3.1 ± 1.5) (P = 0.0002). For the detection of metastatic lesions, the sensitivities of [68 Ga]Ga-FAPI-04 PET and [18F]-FDG PET in 10 patients with regional lymph node metastasis and distant metastasis were 6/10 and 5/10, respectively. CONCLUSION: In this selected cohort, [68 Ga]Ga-FAPI-04 PET had a superior detection rate than [18F]-FDG PET for primary gastric cancer. [68 Ga]Ga-FAPI-04 PET could provide better performance with regard to gastric cancer diagnosis and staging. Prospective clinical trials are warranted.

Changes in brain glucose metabolism and connectivity in somatoform disorders: an 18F-FDG PET study.

Somatoform disorders (SFD) are defined as a syndrome characterized by somatic symptoms which cannot be explained by organic reasons. Chronic or recurrent forms of somatization lead to heavy emotional and financial burden to the patients and their families. However, the underlying etiology of SFD is largely unknown. The purpose of this study is to investigate the changed brain glucose metabolic pattern in SFD. In this study, 18 SFD patients and 21 matched healthy controls were enrolled and underwent an 18F-FDG PET scan. First, we explored the altered brain glucose metabolism in SFD. Then, we calculated the mean 18F-FDG uptake values for 90 AAL regions, and detected the changed brain metabolic connectivity between the most significantly changed regions and all other regions. In addition, the Pearson coefficients between the neuropsychological scores and regional brain 18F-FDG uptake values were computed for SFD patients. We found that SFD patients showed extensive hypometabolism in bilateral superolateral prefrontal cortex, insula, and regions in bilateral temporal gyrus, right angular gyrus, left gyrus rectus, right fusiform gyrus, right rolandic operculum and bilateral occipital gyrus. The metabolic connectivity between right insula and prefrontal areas, as well as within prefrontal areas was enhanced in SFD. And several brain regions were associated with the somatic symptoms, including insula, putamen, middle temporal gyrus, superior parietal gyrus and orbital part of inferior frontal gyrus. Our study revealed widespread alterations of the brain glucose metabolic pattern in SFD patients. Those findings might elucidate the neuronal mechanisms with glucose metabolism and shed light on the pathology of SFD.

Reduced SV2A and GABAA receptor levels in the brains of type 2 diabetic rats revealed by [18F]SDM-8 and [18F]flumazenil PET.

PURPOSE: Type 2 diabetes mellitus (T2DM) is associated with a greater risk of Alzheimer's disease. Synaptic impairment and protein aggregates have been reported in the brains of T2DM models. Here, we assessed whether neurodegenerative changes in synaptic vesicle 2 A (SV2A), γ-aminobutyric acid type A (GABAA) receptor, amyloid-ß, tau and receptor for advanced glycosylation end product (RAGE) can be detected in vivo in T2DM rats. METHODS: Positron emission tomography (PET) using [18F]SDM-8 (SV2A), [18F]flumazenil (GABAA receptor), [18F]florbetapir (amyloid-ß), [18F]PM-PBB3 (tau), and [18F]FPS-ZM1 (RAGE) was carried out in 12-month-old diabetic Zucker diabetic fatty (ZDF) and SpragueDawley (SD) rats. Immunofluorescence staining, Thioflavin S staining, proteomic profiling and pathway analysis were performed on the brain tissues of ZDF and SD rats. RESULTS: Reduced cortical [18F]SDM-8 uptake and cortical and hippocampal [18F]flumazenil uptake were observed in 12-month-old ZDF rats compared to SD rats. The regional uptake of [18F]florbetapir and [18F]PM-PBB3 was comparable in the brains of 12-month-old ZDF and SD rats. Immunofluorescence staining revealed Thioflavin S-negative, phospho-tau-positive inclusions in the cortex and hypothalamus in the brains of ZDF rats and the absence of amyloid-beta deposits. The level of GABAA receptors was lower in the cortex of ZDF rats than SD rats. Proteomic analysis further demonstrated that, compared with SD rats, synaptic-related proteins and pathways were downregulated in the hippocampus of ZDF rats. CONCLUSION: These findings provide in vivo evidence for regional reductions in SV2A and GABAA receptor levels in the brains of aged T2DM ZDF rats.

Brain Functional Alterations and Association with Cognition in People with Preclinical Subjective Cognitive Decline and Objective Subtle Cognitive Difficulties.

Subjective cognitive decline (SCD) and objective subtle cognitive difficulties (Obj-SCD) are considered the initial stages of aberrant cognition prior to mild cognitive impairment (MCI) due to Alzheimer's disease (AD). We aimed to determine the difference of brain function of SCD and Obj-SCD, furthermore, to figure out which one could be the marker of early AD. One hundred and eighty-five participants were enrolled in this study to determine the amyloid pathology and glucose metabolism changes in SCD and Obj-SCD. The association of amyloid deposition and glucose metabolism with cognitive domains were also investigated. Obj-SCD displayed significantly increased amyloid deposition in frontal and temporal lobes compared to SCD and normal cognitive control (NCC). No difference of amyloid deposition between SCD and NCC, and no difference of glucose metabolism among the three groups were observed. Amyloid deposition was associated with function of memory, language and executive domains, and glucose metabolism was only associated with executive function in Obj-SCD. Amyloid deposition was only associated with executive function in SCD. Obj-SCD could be the early stage of AD, which displayed significant increased amyloid deposition, and the increased amyloid deposition was associated with cognitive function in different domains.

Graph Analysis of Functional Brain Topology Using Minimum Spanning Tree in Subjective Cognitive Decline.

BACKGROUND: Subjects with subjective cognitive decline (SCD) are proposed as a potential population to screen for Alzheimer's disease (AD). OBJECTIVE: Investigating brain topologies would help to mine the neuromechanisms of SCD and provide new insights into the pathogenesis of AD. METHODS: Objectively cognitively unimpaired subjects from communities who underwent resting-state BOLD-fMRI and clinical assessments were included. The subjects were categorized into SCD and normal control (NC) groups according to whether they exhibited self-perceived cognitive decline and were worried about it. The minimum spanning tree (MST) of the functional brain network was calculated for each subject, based on which the efficiency and centrality of the brain network organization were explored. Hippocampal/parahippocampal volumes were also detected to reveal whether the early neurodegeneration of AD could be seen in SCD. RESULTS: A total of 49 subjects in NC and 95 subjects in SCD group were included in this study. We found the efficiency and centrality of brain network organization, as well as the hippocampal/parahippocampal volume were preserved in SCD. Besides, SCD exhibited normal cognitions, including memory, language, and execution, but increased depressive and anxious levels. Interestingly, language and execution, instead of memory, showed a significant positive correlation with the maximum betweenness centrality of the functional brain organization and hippocampal/parahippocampal volume. Neither depressive nor anxious scales exhibited correlations with the brain functional topologies or hippocampal/parahippocampal volume. CONCLUSION: SCD exhibited preserved efficiency and centrality of brain organization. In clinical practice, language and execution as well as depression and anxiety should be paid attention in SCD.

Aging-Related Modular Architectural Reorganization of the Metabolic Brain Network.

Background: Modules in brain network represent groups of brain regions that are collectively involved in one or more cognitive domains. Exploring aging-related reorganization of the brain modular architecture using metabolic brain network could further our understanding about aging-related neuromechanism and neurodegenerations. Materials and Methods: In this study, 432 subjects who performed 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) were enrolled and divided into young and old adult groups, as well as female and male groups. The modular architecture was detected, and the connector and hub nodes were identified to explore the topological role of the brain regions based on the metabolic brain network. Results: This study revealed that human metabolic brain network was modular and could be clustered into three modules. The modular architecture was reorganized from young to old ages with regions related to sensorimotor function clustered into the same module; and the number of connector nodes was reduced and most connector nodes were localized in temporo-occipital areas related to visual and auditory functions in old ages. The major gender difference is that the metabolic brain network was delineated into four modules in old female group with the nodes related to sensorimotor function split into two modules. Discussion: Those findings suggest aging is associated with reorganized brain modular architecture. Clinical Trial Registration number: ChiCTR2000036842. Impact statement Distinguishing the basic biology underlying aging from that underlying disease is critical for the prevention, diagnosis, and treatment of the aging-related brain disorders. In this study, we tried to uncover aging-related brain modular reorganization by using metabolic brain network. We found the modular architecture was slightly reorganized from young to old ages with regions related to sensorimotor function more converged. The number of connector nodes was reduced and most connector nodes were localized into the temporo-occipital regions. The major gender difference was that metabolic brain network was delineated into four modules in the old female group with the sensorimotor functions split into two modules.

Alteration of neuroinflammation detected by 18F-GE180 PET imaging in place-conditioned rats with morphine withdrawal.

BACKGROUND: Accumulating evidence indicates that neuroinflammation (NI) significantly contributes to drug addiction, but the conversion of NI after drug withdrawal is not clear. Here, we conducted 18F-flutriciclamide (GE180) positron emission tomography (PET) imaging to investigate the conversion of NI during drug withdrawal and conditioning-induced aversion by measuring the change in microglial activation with 18F-GE180. METHODS: Twelve male adult Sprague-Dawley rats were subjected to morphine withdrawal by the administration of naloxone, and six of them were used to model conditioned place aversion (CPA). 18F-GE180 PET imaging was performed for 11 rats on the last day of the morphine treatment phase and for 10 rats on the response assessment phase of the behavior conditioning procedure. A 18F-GE180 template was established for spatial normalization of each individual image, and the differential 18F-GE180 uptakes between the drug withdrawal (DW) group and the drug addiction (DA) group, the CPA group and the DA group, and the CPA group and the DW group were compared by a voxel-wise two-sample t test using SPM8. RESULTS: Both the DW group and the CPA group spent less time in the conditioning cage during the post-test phase compared with the pretest phase, but only the difference in the CPA group was significant (63.2 ± 34.6 vs. - 159.53 ± 22.02, P < 0.005). Compared with the DA group, the uptake of 18F-GE180 increased mainly in the hippocampus, visual cortex, thalamus and midbrain regions and decreased mainly in the sensory-related cortices after the administration of naloxone in both the DW and CPA groups. Increased 18F-GE180 uptake was only observed in the mesolimbic regions after conditioned aversion compared with the DW group. CONCLUSION: In morphine-dependent rats, Neuroinflammation (NI) became more severe in the addiction-involved brain regions but remitted in the sensory-related brain regions after the administration of naloxone, and this NI induced by withdrawal was further aggravated after conditioned aversion formation thus may help to consolidate the withdrawal memory.

Metabolic Brain Network and Surgical Outcome in Temporal Lobe Epilepsy: A Graph Theoretical Study Based on 18F-fluorodeoxyglucose PET.

Drug-resistant temporal lobe epilepsy (TLE) is a potential candidate for surgery; however, nearly one-third subjects had a poor surgical prognosis. We studied the underlying neuromechanism related to the surgical prognosis using graph theory based on metabolic brain network. Sixty-four unilateral TLE subjects with preoperative 18F-fluorodeoxyglucose (FDG) PET scanning were retrospectively enrolled and divided into Ia (Engel class Ia, n = 32) and non-Ia (Engel class Ib-IV, n = 32) groups according to more than 3-year follow-up after unilateral anterior temporal lobectomy (ATL). The metabolic brain network was constructed and the changed metabolic connectivity of Ia and non-Ia was detected compared with 15 matched healthy controls (HCs). Further, the network properties, including small-worldness and global efficiency, were calculated and hub nodes were also identified for the 3 groups respectively. Non-Ia group exhibited increased connectivity between contralateral fusiform gyrus and contralateral lingual gyrus; while Ia showed decreased connectivity mainly among bilateral frontal, temporal and parietal cortex. Graph theoretical analysis revealed that non-Ia group showed increased small-worldness (35%

The Synaptic Vesicle Protein 2A Interacts With Key Pathogenic Factors in Alzheimer's Disease: Implications for Treatment.

Alzheimer's disease (AD), a serious neurodegenerative disease, is pathologically characterized by synaptic loss and dysfunction. Synaptic vesicle protein 2A (SV2A) is an indispensable vesicular protein specifically expressed in synapses and can be used as a biomarker for synaptic density. We found that the expression of SV2A was down-regulated in the hippocampus of AD patients, yet the relation of SV2A to other hallmarks of AD pathology such as amyloid precursor protein (APP), ß-amyloid (Aß), and Tau protein is not thoroughly clear. In addition, SV2A colocalized with APP and was down-regulated at Aß deposition. Moreover, we found that SV2A deficiency leads to a simultaneous increase in Aß and Tau hyperphosphorylation, while SV2A overexpression was associated with downregulation of ß-site APP cleaving enzyme 1 and apolipoprotein E genes. In addition, evidence gained in the study points to the phosphatidylinositol 3-kinase signaling pathway as a possible mediator in SV2A regulation influencing the incidence and development of AD. With limited effective diagnostic methods for AD, a close interplay between SV2A and AD-related proteins demonstrated in our study may provide novel and innovative diagnostic and therapeutic opportunities.

Positron Emission Computed Tomography Imaging of Synaptic Vesicle Glycoprotein 2A in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disorder seen in age-dependent dementia. There is currently no effective treatment for AD, which may be attributed in part to lack of a clear underlying mechanism. Early diagnosis of AD is of great significance to control the development of the disease. Synaptic loss is an important pathology in the early stage of AD, therefore the measurement of synaptic density using molecular imaging technology may be an effective way to early diagnosis of AD. Synaptic vesicle glycoprotein 2A (SV2A) is located in the presynaptic vesicle membrane of virtually all synapses. SV2A Positron Emission Computed Tomography (PET) could provide a way to measure synaptic density quantitatively in living humans and to track changes in synaptic density in AD. In view of the fact that synaptic loss is the pathology of both epilepsy and AD, this review summarizes the potential role of SV2A in the pathogenesis of AD, and suggests that SV2A should be used as an important target molecule of PET imaging agent for the early diagnosis of AD.

18F-Labelled pyrrolopyrimidines reveal brain leucine-rich repeat kinase 2 expression implicated in Parkinson's disease.

18F-Labelled pyrrolopyrimidines were synthesized and evaluated as positron emission tomography (PET) probes to determine leucine-rich repeat kinase 2 (LRRK2) expression in the brain. With pyrrolopyrimidine derivative PF-06447475 as the lead compound, two in vivo-stable 18F-labelled pyrrolopyrimidines ([18F]1 and [18F]2) were synthesized automatically at radiochemical yields 8-10% (non-decay-corrected) with molar activities of 0.95 and 0.5 GBq/µmol, respectively. The measured Kd of 6.90 nM for 1 and 14.27 nM for 2 demonstrated high affinities for LRRK2. The LRRK2 G2019S mice had higher uptakes (P < 0.01) of [18F]1 in the olfactory bulb, striatum, and hippocampus than WT mice during microPET/CT imaging, consistent with immunohistology results of LRRK2 distribution. [11C]CFT microPET/CT imaging demonstrated a lower expression of dopamine transporter in LRRK2 G2019S mice. Parkinson's disease-like deficits in dopamine transporter synthesis and cognitive declines were noticed along with LRRK2 expression increase in the olfactory bulb, striatum, and hippocampus. Therefore, 18F-labelled pyrrolopyrimidines can reflect real-time LRRK2 expression changes implicated in Parkinson's disease, which paves the way for LRRK2-related neurodegenerative precise therapy.

Neuroprotection of Exendin-4 by Enhanced Autophagy in a Parkinsonian Rat Model of α-Synucleinopathy.

Glucagon-like peptide-1 (GLP-1) receptor stimulation ameliorates parkinsonian motor and non-motor deficits in both experimental animals and patients; however, the disease-modifying mechanisms of GLP-1 receptor activation have remained unknown. The present study investigated whether exendin-4 (a GLP-1 analogue) can rescue motor deficits and exert disease-modifying effects in a parkinsonian rat model of α-synucleinopathy. This model was established by unilaterally injecting AAV-9-A53T-α-synuclein into the right substantia nigra pars compacta, followed by 4 or 8 weeks of twice-daily intraperitoneal injections of exendin-4 (5 µg/kg/day) starting at 2 weeks after AAV-9-A53T-α-synuclein injections. Positron emission tomography/computed tomography (PET/CT) scanning and immunostaining established that treatment with exendin-4 attenuated tyrosine-hydroxylase-positive neuronal loss and terminal denervation and mitigated the decrease in expression of vesicular monoamine transporter 2 within the nigrostriatal dopaminergic systems of rats injected with AAV-9-A53T-α-synuclein. It also mitigated the parkinsonian motor deficits assessed in behavioral tests. Furthermore, through both in vivo and in vitro models of Parkinson's disease, we showed that exendin-4 promoted autophagy and mediated degradation of pathological α-synuclein, the effects of which were counteracted by 3-methyladenine or chloroquine, the autophagic inhibitors. Additionally, exendin-4 attenuated dysregulation of the PI3K/Akt/mTOR pathway in rats injected with AAV-9-A53T-α-synuclein. Taken together, our results demonstrate that exendin-4 treatment relieved behavioral deficits, dopaminergic degeneration, and pathological α-synuclein aggregation in a parkinsonian rat model of α-synucleinopathy and that these effects were mediated by enhanced autophagy via inhibiting the PI3K/Akt/mTOR pathway. In light of the safety and tolerance of exendin-4 administration, our results suggest that exendin-4 may represent a promising disease-modifying treatment for Parkinson's disease.

Maturation of topological organization of brain networks in male adolescent rats: A longitudinal FDG-PET study.

Recent studies have found developmental alterations of the brain during the adolescent period. However, maturation-related changes of the topological properties in brain networks are unexplored so far. We therefore used fluoro-d-glucose positron emission tomography (FDG PET) to explore the maturation-related topological metabolic changes in brain networks from adolescence to adulthood with a longitudinal study in rats (male, n = 6), followed by a graph theoretical analysis. Our results showed reduced normalization characteristic path length and increased small world index of brain networks. Specifically, we found that relative to adulthood, in the adolescent stage rats had significantly increased nodal centrality in right entorhinal cortex, left frontal association cortex, and cerebellum, areas relating to memory, executive function and higher cognitive control and motor control; and significantly reduced nodal centrality in left superior colliculus and left retrosplenial cortex. These findings suggest that moving from adolescence to adulthood, networks of the brain mature accompanied by reassignment of hub regions to increase network efficiency. These results provide an animal model of brain network maturation from adolescence to adulthood which are relevant for understanding of development of psychiatric disorders during adolescence or transition from adolescence to adulthood.

Decreased striatal vesicular monoamine transporter 2 (VMAT2) expression in a type 1 diabetic rat model: A longitudinal study using micro-PET/CT.

AIMS: Diabetes mellitus is a risk factor for Parkinson's disease. These diseases share similar pathogenic pathways, such as mitochondrial dysfunction, inflammation, and altered metabolism. Despite these similarities, the pathogenic relationship between these two diseases is unclear. [18F]FP-(+)-DTBZ is a promising radiotracer targeting VMAT2, which has been used to measure ß-cell mass and to diagnose Parkinson's disease. The aim of this study was to examine the effect of type 1 diabetes on VMAT2 expression in the striatum using [18F]FP-(+)-DTBZ. MATERIALS AND METHODS: A longitudinal study of type 1 diabetic rats was established by intraperitoneally injecting male Wistar rats with streptozotocin. Rats injected with saline were used as the control group. Glucose level, body weight, and [18F]FP-(+)-DTBZ uptake in the striatum and pancreas were evaluated at 0.5, 1, 4, 6 and 12 months after STZ or saline injection. RESULTS: At one-half month post-STZ injection, the glucose levels in these rats increased and then returned to a normal level at 6 months. Along with increased glucose levels, body weight was also decreased significantly and returned slowly to a normal level. ß-Cell mass and striatal [18F]FP-(+)-DTBZ uptake were impaired significantly at 2 weeks post-STZ injection in type 1 diabetic rats and returned to a normal level at 6 and 4 months post-STZ injection. CONCLUSIONS: Due to increased glucose levels and decreased ß-cell mass, decreased [18F]FP-(+)-DTBZ uptake in the striatum was observed in type 1 diabetic rats. Decreased BCM and increased glucose levels were correlated with VMAT2 expression in the striatum which indicated DM is a risk factor for PD.

A novel PET tracer 18F-deoxy-thiamine: synthesis, metabolic kinetics, and evaluation on cerebral thiamine metabolism status.

BACKGROUND: Some neuropsychological diseases are associated with abnormal thiamine metabolism, including Korsakoff-Wernicke syndrome and Alzheimer's disease. However, in vivo detection of the status of brain thiamine metabolism is still unavailable and needs to be developed. METHODS: A novel PET tracer of 18F-deoxy-thiamine was synthesized using an automated module via a two-step route. The main quality control parameters, such as specific activity and radiochemical purity, were evaluated by high-performance liquid chromatography (HPLC). Radiochemical concentration was determined by radioactivity calibrator. Metabolic kinetics and the level of 18F-deoxy-thiamine in brains of mice and marmosets were studied by micro-positron emission tomography/computed tomography (PET/CT). In vivo stability, renal excretion rate, and biodistribution of 18F-deoxy-thiamine in the mice were assayed using HPLC and γ-counter, respectively. Also, the correlation between the retention of cerebral 18F-deoxy-thiamine in 60 min after injection as represented by the area under the curve (AUC) and blood thiamine levels was investigated. RESULTS: The 18F-deoxy-thiamine was stable both in vitro and in vivo. The uptake and clearance of 18F-deoxy-thiamine were quick in the mice. It reached the max standard uptake value (SUVmax) of 4.61 ± 0.53 in the liver within 1 min, 18.67 ± 7.04 in the kidney within half a minute. The SUV dropped to 0.72 ± 0.05 and 0.77 ± 0.35 after 60 min of injection in the liver and kidney, respectively. After injection, kidney, liver, and pancreas exhibited high accumulation level of 18F-deoxy-thiamine, while brain, muscle, fat, and gonad showed low accumulation concentration, consistent with previous reports on thiamine distribution in mice. Within 90 min after injection, the level of 18F-deoxy-thiamine in the brain of C57BL/6 mice with thiamine deficiency (TD) was 1.9 times higher than that in control mice, and was 3.1 times higher in ICR mice with TD than that in control mice. The AUC of the tracer in the brain of marmosets within 60 min was 29.33 ± 5.15 and negatively correlated with blood thiamine diphosphate levels (r = - 0.985, p = 0.015). CONCLUSION: The 18F-deoxy-thiamine meets the requirements for ideal PET tracer for in vivo detecting the status of cerebral thiamine metabolism.

Rapid one-step 18F-radiolabeling of biomolecules in aqueous media by organophosphine fluoride acceptors.

Currently, only a few 18F-radiolabeling methods were conducted in aqueous media, with non-macroelement fluoride acceptors and stringent conditions required. Herein, we describe a one-step non-solvent-biased, room-temperature-driven 18F-radiolabeling methodology based on organophosphine fluoride acceptors. The high water tolerance for this isotope-exchange-based 18F-labeling method is attributed to the kinetic and thermodynamic preference of F/F over the OH/F substitution based on computational calculations and experimental validation. Compact [18/19F]di-tert-butyl-organofluorophosphine and its derivatives used as 18F-labeling synthons exhibit excellent stability in vivo. The synthons are further conjugated to several biomolecular ligands such as c(RGDyk) and human serum albumin. The one-step labeled biomolecular tracers demonstrate intrinsic target imaging ability and negligible defluorination in vivo. The current method thus offers a facile and efficient 18F-radiolabeling pathway, enabling further widespread application of 18F.

Evaluation of Neuropathic Pain in a Rat Model of Total Brachial Plexus Avulsion from Behavior to Brain Metabolism.

BACKGROUND: Approximately 30% to 80% of patients with brachial plexus avulsion (BPA) developed neuropathic pain. It is an intolerable neuropathic pain, which brings heavy burden to family and society. In addition to motor and sensory deficits, neuropathic pain can be another serious sequela that equally influences the patient. The development of a microsurgical technique has promoted the treatment and rehabilitation of brachial plexus injury, but pain relief after BPA is still a difficult problem. OBJECTIVES: The present study aimed to semi-quantify changes in the behavior, spinal cord and cerebral metabolism in a neuropathic pain model following BPA injury in rats. STUDY DESIGN: Controlled animal study. SETTING: Institute of Rehabilitation Medicine, Shanghai, China. METHODS: A total of 15 Sprague-Dawley rats, weighing 200 to 220 g, were randomly divided into 2 groups: experimental group (n = 10) and control group (n = 5). In the experimental group, neuropathic pain induced by BPA was established by directly avulsing the C5, C6, C7, C8, and T1 roots on the right side from the spinal cord. Rats in the control group only received open-close surgery. The autotomic behavior of biting their own digits was recorded and scored at 2 months after the surgery. Small animal positron emission tomography/computed tomography (PET/CT) images after injection of a 2-[18F]-fluoro-2-deoxy-D-glucose (18F-FDG) tracer were acquired to evaluate glucose metabolism in pain-related brain regions before and after the surgery, respectively. Semi-quantitative values of cortical to cerebellum standardized uptake value (SUV) ratios were calculated. Then, the animals were euthanized and the cervical segments of the spinal cord were removed for detection of glial fibrillary acidic protein (GFAP) expression in the astrocytes by immunohistochemical assay. RESULTS: Nine of the 10 rats (90%) in the experimental group showed autotomic behavior at 2 months after the surgery. Slight autotomic behavior was noted only in one of 5 rats (20%) from the control group. The autotomic score in the experimental group was significantly higher than that in the control group (5.4 ± 1.0 vs. 0.2 ± 0.4, P < 0.05). The experimental group showed significantly higher SUV ratio in both the right and left thalamus, compared to the control group (P < 0.05). Immunohistochemical assay demonstrated that GFAP positive astrocytes in the dorsal horn at the injured side significantly increased compared to the control group (P < 0.05). LIMITATIONS: There are differences between small animals and human beings, and the structure and function of the human brain is more complex than in rodents. Therefore, extrapolation of the present conclusion should be cautious. CONCLUSIONS: The present study reported a unique model of neuropathic pain following total BPA in rodents, which was demonstrated by a higher rate and score of autotomic behavior. More astrocytes were found activated in the spinal cord at the corresponding level of C5 and C6 spinal cord. In the small animal PET/CT imaging, significantly higher standardized glucose metabolic activity was found in both the right and left thalamus in the experimental group. The present study semi-quantified the neuropathic pain behavior in rats and explored the plastic changes in the spinal and brain metabolism. KEY WORDS: Brachial plexus avulsion, small animal PET/CT, glucose metabolism, neuropathic pain, astrocyte, 18F-FDG.