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Purpose: Toludesvenlafaxine is a recently developed antidepressant that belongs to the triple reuptake inhibitor class. Despite the in vitro evidence that toludesvenlafaxine inhibits the reuptake of serotonin (5-HT), norepinephrine (NE) and dopamine (DA), there is no in vivo evidence that toludesvenlafaxine binds to DAT and increases DA level, a mechanism thought to contribute to its favorable clinical performance. Methods: Positron emission tomography/computed tomography (PET/CT) was used to examine the DAT binding capacity in healthy rats and human subjects and microdialysis was used to examine the striatal DA level in rats. [18F]FECNT and [11C]CFT were used as PET/CT radioactive tracer for rat and human studies, respectively. Results: In rats, 9 mg/kg of toludesvenlafaxine hydrochloride (i.v.) followed by an infusion of 3 mg/kg via minipump led to the binding rate to striatum DAT at 3.7 – 32.41% and to hypothalamus DAT at 5.91 – 17.52% during the 45 min scanning period. 32 mg/kg oral administration with toludesvenlafaxine hydrochloride significantly increased the striatal DA level with the AUC0 − 180 min increased by 63.9%. In healthy volunteers, 160 mg daily toludesvenlafaxine hydrochloride sustained-release tablets for 4 days led to an average occupancy rates of DAT at 8.04% ± 7.75% and 8.09% ± 7.00%, respectively, in basal ganglion 6 h and 10 h postdose. Conclusion: These results represent the first to confirm the binding of toludesvenlafaxine to DAT in both rats and humans using PET/CT, and its elevation of brain DA level, which may help understand the unique pharmacological and functional effects of triple reuptake inhibitors such as toludesvenlafaxine. ClinicalTrials.gov identifiers: : NCT05905120. Registered 14 June 2023. (retrospectively registered). [ABSTRACT FROM AUTHOR]

Purpose: The cluster of differentiation (CD70) is a potential biomarker of clear cell renal cell carcinoma (ccRCC). This study aims to develop CD70-targeted immuno-positron emission tomography/computed tomography (immunoPET/CT) imaging tracers and explore the diagnostic value in preclinical studies and the potential value in detecting metastases in ccRCC patients. Methods: Four novel CD70-specific single-domain antibodies (sdAbs) were produced and labelled with 18F by the aluminium fluoride restrained complexing agent (AlF-RESCA) method to develop radiotracers. The visualisation properties of the tracers were evaluated in a subcutaneous ccRCC patient–derived xenograft (PDX) model. In a registered prospective clinical trial (NCT06148220), six patients with pathologically confirmed RCC were included and underwent immunoPET/CT examination exploiting one of the developed tracers (i.e., [18F]RCCB6). Results: We engineered four sdAbs (His-tagged RCCB3 and RCCB6, His-tag-free RB3 and RB6) specifically targeting recombinant human CD70 without cross-reactivity to murine CD70. ImmunoPET/CT imaging with [18F]RCCB3 and [18F]RCCB6 demonstrated a high tumour-to-background ratio in a subcutaneous ccRCC PDX model, with the latter showing better diagnostic potential supported by higher tumour uptake and lower bone accumulation. In comparison, [18F]RB6, developed by sequence optimisation, has significantly lower kidney accumulation than that of [18F]RCCB6. In a pilot translational study, [18F]RCCB6 immunoPET/CT displayed ccRCC metastases in multiple patients and demonstrated improved imaging contrast and diagnostic value than 18F-FDG PET/CT in a patient with ccRCC. Conclusion: The work successfully developed a series of CD70-targeted immunoPET/CT imaging tracers. Of them, [18F]RCCB6 clearly and specifically identified inoculated ccRCCs in preclinical studies. Clinical translation of [18F]RCCB6 suggests potential for identifying recurrence and/or metastasis in ccRCC patients. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

INTRODUCTION: The objective of this study is to investigate the incremental value of amyloid positron emission tomography (Aβ‐PET) in a tertiary memory clinic setting in China. METHODS: A total of 1073 patients were offered Aβ‐PET using 18F‐florbetapir. The neurologists determined a suspected etiology (Alzheimer's disease [AD] or non‐AD) with a percentage estimate of their confidence and medication prescription both before and after receiving the Aβ‐PET results. RESULTS: After disclosure of the Aβ‐PET results, etiological diagnoses changed in 19.3% of patients, and diagnostic confidence increased from 69.3% to 85.6%. Amyloid PET results led to a change of treatment plan in 36.5% of patients. Compared to the late‐onset group, the early‐onset group had a more frequent change in diagnoses and a higher increase in diagnostic confidence. DISCUSSION: Aβ‐PET has significant impacts on the changes of diagnoses and management in Chinese population. Early‐onset cases are more likely to benefit from Aβ‐PET than late‐onset cases. Highlights: Amyloid PET contributes to diagnostic changes and its confidence in Chinese patients.Amyloid PET leads to a change of treatment plans in Chinese patients.Early‐onset cases are more likely to benefit from amyloid PET than late‐onset cases. [ABSTRACT FROM AUTHOR]

The Category Switching Test (CaST) is a verbal fluency test with active semantic category switching. This study aimed to explore the association between CaST performance and brain amyloid-β (Aβ) burden in patients with mild cognitive impairment (MCI) and the neurofunctional mechanisms. A total of 112 participants with MCI underwent Florbetapir positron emission tomography, resting-state functional magnetic resonance imaging, and a neuropsychological test battery. The high Aβ burden group had worse CaST performance than the low-burden group. CaST score and left middle temporal gyrus fractional amplitude of low-frequency fluctuations (fALFF) related inversely to the global Florbetapir standardized uptake value rate. Functional connectivity between the left middle temporal gyrus and frontal lobe decreased widely and correlated with CaST score in the high Aβ burden group. Thus, CaST score and left middle temporal gyrus fALFF were valuable in discriminating high Aβ burden. CaST might be useful in screening for MCI with high Aβ burden. [ABSTRACT FROM AUTHOR]

Background: Gender, APOE ɛ4 status and age have different effects on brain amyloid deposition in patients with mild cognitively impaired (MCI). Objective: To investigate the effect of gender×APOE ɛ4 status interaction on Aβ deposition in the brains of individuals with MCI in different age groups by PET scanning. Methods: 204 individuals with MCI were classified into younger or older groups based on whether they were under or over 65 years of age. APOE genotyping, structural MRI, amyloid PET scans, and neuropsychological tests were performed. The effect of gender×APOE ɛ4 status interaction on Aβ deposition was assessed in different age groups. Results: APOE ɛ4 carriers had higher amyloid deposition than noncarriers in the whole group. Females with MCI had more amyloid deposition in the medial temporal lobe than males in the whole cohort and younger group. Older individuals with MCI had higher amyloid deposition than younger individuals. In stratified analysis by age, female APOE ɛ4 carriers had significantly increased amyloid deposition compared to their male counterparts only in the medial temporal lobe in the younger group. Amyloid deposition was increased in female APOE ɛ4 carriers compared to noncarriers in the younger group, whereas higher amyloid deposition was observed in male APOE ɛ4 carriers in the older group. Conclusion: Women in the younger group with MCI who were APOE ɛ4 carriers had more amyloid deposition in the brain, while men in the older group with MCI who were APOE ɛ4 carriers had higher amyloid deposition. [ABSTRACT FROM AUTHOR]

Purpose: The presence and functional competence of intratumoral CD8+ T cells is often a barometer for successful immunotherapeutic responses in cancer. Despite this understanding and the extensive number of clinical-stage immunotherapies focused on potentiation (co-stimulation) or rescue (checkpoint blockade) of CD8+ T cell antitumor activity, dynamic biomarker strategies are often lacking. To help fill this gap, immuno-PET nuclear imaging has emerged as a powerful tool for in vivo molecular imaging of antibody targeting. Here, we took advantage of immuno-PET imaging using 89Zr-IAB42M1-14, anti-mouse CD8 minibody, to characterize CD8+ T-cell tumor infiltration dynamics following ICOS (inducible T-cell co-stimulator) agonist antibody treatment alone and in combination with PD-1 blocking antibody in a model of mammary carcinoma. Procedures. Female BALB/c mice with established EMT6 tumors received 10 µg, IP of either IgG control antibodies, ICOS agonist monotherapy, or ICOS/PD-1 combination therapy on days 0, 3, 5, 7, 9, 10, or 14. Imaging was performed at 24 and 48 h post IV dose of 89Zr IAB42M1-14. In addition to 89Zr-IAB42M1-14 uptake in tumor and tumor-draining lymph node (TDLN), 3D radiomic features were extracted from PET/CT images to identify treatment effects. Imaging mass cytometry (IMC) and immunohistochemistry (IHC) was performed at end of study. Results: 89Zr-IAB42M1-14 uptake in the tumor was observed by day 11 and was preceded by an increase in the TDLN as early as day 4. The spatial distribution of 89Zr-IAB42M1-14 was more uniform in the drug treated vs. control tumors, which had spatially distinct tracer uptake in the periphery relative to the core of the tumor. IMC analysis showed an increased percentage of cytotoxic T cells in the ICOS monotherapy and ICOS/PD-1 combination group compared to IgG controls. Additionally, temporal radiomics analysis demonstrated early predictiveness of imaging features. Conclusion: To our knowledge, this is the first detailed description of the use of a novel immune-PET imaging technique to assess the kinetics of CD8+ T-cell infiltration into tumor and lymphoid tissues following ICOS agonist and PD-1 blocking antibody therapy. By demonstrating the capacity for increased spatial and temporal resolution of CD8+ T-cell infiltration across tumors and lymphoid tissues, these observations underscore the widespread potential clinical utility of non-invasive PET imaging for T-cell-based immunotherapy in cancer. [ABSTRACT FROM AUTHOR]

Background: Subjective cognitive decline (SCD) is a self-perceived decline in cognitive ability, which exhibits no objective impairment but increased risk of conversion to mild cognitive impairment and Alzheimer's disease (AD). Objective: To investigate how influencing factors (risk gene, age, sex, and education) affect amyloid-β (Aβ) deposition and gray matter (GM) atrophy in SCD population. Methods: 281 SCD subjects were included in this study, who underwent clinical evaluation, cognitive ability assessment, apolipoprotein E (APOE) genotyping, 18F-Florbetapir positron emission computed tomography, and magnetic resonance imaging screening. Two-sample t tests and analysis of variance were performed based on voxel-wise outcome. Results: In 281 SCD subjects with an average age of 63.86, 194 subjects (69.04%) were females, and 56 subjects carried APOE ɛ4 genes. Statistical results revealed APOE ɛ4 gene, age, and sex influenced Aβ deposition in different brain regions; moreover, only the interaction exhibited between age and APOE ɛ4 genes. The GM atrophy of hippocampal, amygdala, precentral, and occipital lobes occurred in the group age over 60. The GM volume of the hippocampal, frontal, and occipital lobe in females was less than males. Education had an effect only on cognitive function. Conclusion: In SCD, APOE ɛ4 gene, age, and sex significantly influenced Aβ deposition and APOE ɛ4 gene can interact with age in impacting Aβ deposition. Both age and sex can affect GM atrophy. The results suggested that female SCD with APOE ɛ4 genes and aged more than 60 years old might exhibit advanced AD biomarkers. [ABSTRACT FROM AUTHOR]

Objective: In this study, we investigated the role of [68Ga]Ga-FAPI PET imaging in the detection of primary and metastatic gastric signet-ring-cell carcinoma (GSRCC) and compared with [18F]FDG PET. Methods: This retrospective multicenter analysis included 34 patients with histologically confirmed GSRCCs from four medical centers. The maximum standard uptake value (SUVmax), tumor-to-background ratio (TBR), and diagnostic accuracy were compared between the two modalities. [18F]FDG and [68Ga]Ga-FAPI uptakes were compared by using the Wilcoxon signed-rank test. McNemar's test was used to compare the diagnostic accuracy between the two techniques. Results: Data were analyzed from 27 paired PET/CT and 7 paired PET/MRI scans for 34 GSRCC patients (16 men and 18 women) who had a median age of 51 years (range: 25–85 years). [68Ga]Ga-FAPI PET showed higher SUVmax and TBR values than did [18F]FDG PET in the primary tumors (SUVmax: 5.2 vs. 2.2, p = 0.001; TBR: 7.6 vs. 1.3, p < 0.001), involved lymph nodes (SUVmax: 6.8 vs. 2.5, p < 0.001; TBR: 5.8 vs. 1.3, p < 0.001), and bone and visceral metastases (SUVmax: 6.5 vs. 2.4, p < 0.001; TBR: 6.3 vs. 1.3, p < 0.001). In diagnostic performance, [68Ga]Ga-FAPI PET exhibited higher sensitivity than [18F]FDG PET for detecting primary tumors (73% [16/22] vs. 18% [4/22], p < 0.001), local recurrences (100% [7/7] vs. 29% [2/7], p = 0.071), lymph node metastases (77% [59/77] vs. 23% [18/77], p < 0.001), and distant metastases (93% [207/222] vs. 39% [86/222], p < 0.001). Conclusion: The results from this multicenter retrospective analysis justify the clinical use of [68Ga]Ga-FAPI tracers for GSRCC diagnosis and staging. Key Points: • [68Ga]Ga-FAPI PET/CT is a promising imaging modality for the detection of primary and metastatic disease and has implications for TNM staging in GSRCC. • In this multicenter study of 34 patients with GSRCC, [68Ga]Ga-FAPI PET exhibited greater radiotracer uptake, tumor-to-background ratios, and diagnostic accuracy than [18F]FDG PET for detecting primary/recurrent tumors and metastatic lesions. [ABSTRACT FROM AUTHOR]

An editorial is presented which argues positron emission tomography could accurately detect hydrogen sulfide in brain pathophysiology, opening a new horizon for detecting neuroinflammation by mapping hydrogen sulfide level. It also discusses the neuroinfammation is a key biological process in response to cell infection or injury that involves all the cells present within the central nervous system including microglia, astrocytes, neurons, and macroglia.

Plasma amyloid-β (Aβ) was associated with brain Aβ deposition and Alzheimer's disease (AD) development. However, changes of plasma Aβ over the course of cognitive decline in the Alzheimer's continuum remained uncertain. We recruited 449 participants to this study, including normal controls (NC), subjective cognitive decline (SCD), mild cognitive impairment (MCI), AD, and non-AD dementia. All the participants underwent plasma Aβ42, Aβ40, and t-tau measurements with single-molecule array (Simoa) immunoassay and PET scan with 18F-florbetapir amyloid tracer. In the subgroup of Aβ-PET positive, plasma Aβ42 and Aβ42/Aβ40 ratio was significantly lower in AD than NC, SCD and MCI, yet SCD had significantly higher levels of plasma Aβ42 than both NC and MCI. In the diagnostic groups of MCI and dementia, participants with Aβ-PET positive had lower plasma Aβ42 and Aβ42/40 ratio than participants with Aβ-PET negative, and the increasing levels of plasma Aβ42 and Aβ42/40 ratio indicated lower risks of Aβ-PET positive. However, in the participants with SCD, plasma Aβ42 and Aβ40 were higher in the subgroup of Aβ-PET positive than Aβ-PET negative, and the increasing levels of plasma Aβ42 and Aβ40 indicated higher risks of Aβ-PET positive. No significant association was observed between plasma Aβ and Aβ-PET status in normal controls. These findings showed that, in the continuum of AD, plasma Aβ42 had a significantly increasing trend from NC to SCD before decreasing in MCI and AD. Furthermore, the predictive values of plasma Aβ for brain amyloid deposition were inconsistent over the course of cognitive decline. [ABSTRACT FROM AUTHOR]

Urine-based formaldehyde has been reported to be a potential biomarker for Alzheimer's disease (AD). However, there is a lack of research about the correlation between urine formaldehyde and cognitive abilities in the clinical spectrum of AD, especially the preclinical period. The relationship of urine formaldehyde with APOE genotype, brain Aβ status and plasma pathological markers in AD are also not clear. This study intends to explore the correlation between urine formaldehyde and cognitive abilities throughout the AD continuum, to evaluate the role of APOE genotype and Aβ accumulation on urine formaldehyde, and further to clarify the relationship between urine formaldehyde level and AD plasma pathological markers. We recruited 72 cognitively normal controls (NC), 110 subjective cognitive decline (SCD), 140 objectively defined subtle cognitive decline (Obj-SCD), 171 mild cognitive impairment (MCI) and 136 AD dementia participants. Next, we collected the data of clinical materials, neuropsychological examination, APOE genotyping, urine formaldehyde concentration, 18F-florbetapir PET imaging and plasma biomarkers. Compared with NC, Obj-SCD and MCI groups, the level of urine formaldehyde was found to be significantly upregulated in SCD group. In addition, the level of urine formaldehyde was significantly higher in AD group compared to both NC and MCI groups. Further subgroup analysis showed that, the level of urine formaldehyde was higher in APOE ε4+ subgroup compared to APOE ε4– subgroup in both NC and AD groups. There was no difference in urine formaldehyde level between the brain Aβ+ subgroup and Aβ– subgroup in each group. In addition, regression analysis showed urine formaldehyde level was correlated with gender, plasma Aβ42 and p-Tau181/T-tau. The dynamic change of urine formaldehyde in the AD continuum could be used as a potential biomarker, and combined with comprehensive cognitive evaluation could become a useful method to distinguish SCD from NC and Obj-SCD, and to distinguish MCI from AD. [ABSTRACT FROM AUTHOR]

Background: To test the advantages of positron emission tomography and computed tomography (PET/CT) for diagnosing lymph nodes and staging nasopharyngeal carcinoma and to investigate its benefits for survival and treatment decisions. Methods: The performance of PET/CT and magnetic resonance imaging (MRI) in diagnosis was compared based on 460 biopsied lymph nodes. Using the propensity matching method, survival differences of T3N1M0 patients with (n = 1093) and without (n = 1377) PET/CT were compared in diverse manners. A radiologic score model was developed and tested in a subset of T3N1M0 patients. Results: PET/CT performed better than MRI with higher sensitivity, accuracy, and area under the receiver operating characteristic curve (96.7% vs. 88.5%, p < 0.001; 88.0% vs. 81.1%, p < 0.001; 0.863 vs. 0.796, p < 0.05) in diagnosing lymph nodes. Accordingly, MRI-staged T3N0-3M0 patients showed nondifferent survival rates, as they were the same T3N1M0 if staged by PET/CT. In addition, patients staged by PET/CT and MRI showed higher survival rates than those staged by MRI alone (p < 0.05), regardless of the Epstein-Barr virus DNA load. Interestingly, SUVmax-N, nodal necrosis, and extranodal extension were highly predictive of survival. The radiologic score model based on these factors performed well in risk stratification with a C-index of 0.72. Finally, induction chemotherapy showed an added benefit (p = 0.006) for the high-risk patients selected by the model but not for those without risk stratification (p = 0.78). Conclusion: PET/CT showed advantages in staging nasopharyngeal carcinoma due to a more accurate diagnosis of lymph nodes and this contributed to a survival benefit. PET/CT combined with MRI provided prognostic factors that could identify high-risk patients and guide individualized treatment. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Molecular imaging, including positron emission tomography (PET) and single photon emission computed tomography (SPECT), along with functional and structural imaging by magnetic resonance imaging, provides precision approaches to facilitate the diagnosis of neurogenerative diseases [[3]-[5]]. Amyloid and tau PET imaging has demonstrated the clinical utility, providing tools to evaluate the disease stages, improve the diagnostic accuracy, and monitor the efficacy of interventions. The prevalence and incidence of neurogenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are rapidly increasing with the aging society [[1]]. [Extracted from the article]

Alzheimer's Disease (AD), the leading cause of senile dementia, is a progressive neurodegenerative disorder affecting millions of people worldwide and exerting tremendous socioeconomic burden on all societies. Although definitive diagnosis of AD is often made in the presence of clinical manifestations in late stages, it is now universally believed that AD is a continuum of disease commencing from the preclinical stage with typical neuropathological alterations appearing decades prior to its first symptom, to the prodromal stage with slight symptoms of amnesia (amnestic mild cognitive impairment, aMCI), and then to the terminal stage with extensive loss of basic cognitive functions, i.e., AD-dementia. Positron emission tomography (PET) radiotracers have been developed in a search to meet the increasing clinical need of early detection and treatment monitoring for AD, with reference to the pathophysiological targets in Alzheimer's brain. These include the pathological aggregations of misfolded proteins such as β-amyloid (Aβ) plagues and neurofibrillary tangles (NFTs), impaired neurotransmitter system, neuroinflammation, as well as deficient synaptic vesicles and glucose utilization. In this article we survey the various PET radiotracers available for AD imaging and discuss their clinical applications especially in terms of early detection and cognitive relevance. [ABSTRACT FROM AUTHOR]

Background: Brain development and maturation in adolescence is a complex process with active changes of metabolic and neurotransmission pathways. Positron emission tomography (PET) is a useful imaging modality for tracking metabolic and functional changes in adolescent brain. In this study, changes of glucose metabolism, expression of vesicular monoamine transporter 2 and dopamine transporter during adolescent brain development in rats were investigated with PET/CT. Methods: A longitudinal PET/CT study of age-dependent changes of VMAT2, DAT and glucose metabolism in adolescent brain was conducted in a group of Wistar rats (n = 6) post sequential intravenous injection of 18F-PF-(+)-DTBZ, 11C-CFT, and 18F-FDG, respectively. PET acquisition was performed at 2, 4, 9, and 12 months of age. Radiotracer uptake in different brain regions, including the striatum, cerebellum, and hippocampus, were quantified and recorded as Standardized uptake value (SUV) and striatal specific uptake ratio (SUVR: SUV in brain regions/SUV in cerebellum). Results: Variable uptake of 18F-PF-(+)-DTBZ and 11C-CFT were detected, with highest level uptake in the striatum and accumbens. There was significant age-dependent increase of 18F-PF-(+)-DTBZ and 11C-CFT uptake in the striatum from 2 months of age (SUV: 1.36 ± 0.22, 1.37 ± 0.39, respectively), to 4 months (SUV: 2.22 ± 0.29, 2.04 ± 0.33), 9 months (1.98 ± 0.34, 2.09 ± 0.18), 12 months (SUV: 1.93 ± 0.19, 2.00 ± 0.17) of age, SUV of 18F-FDG also increased from 2 months of age to older ages (SUV in the striatum: 3.71 ± 0.78 at 2 month, 5.28 ± 0.81, 5.14 ± 0.73, 4.94 ± 0.50 at 4, 9, 12 month, respectively). Conclusion: Age-dependent increases of striatal of 18F-FDG, 18F-PF-(+)-DTBZ, and 11C-CFT uptake were detected in rats from 2 to 4 month of age, demonstrating striatal development presents over the first 4 months of age. Four months of age can be considered a safe threshold to launch brain disease studies for exclusion of confusion of continuing tissue development. These findings support further investigation of age-dependent changes in expression of DAT, VMAT2, and glucose metabolism for their potential use as a new imaging biomarker for study of brain development and functional maturation. [ABSTRACT FROM AUTHOR]

Copper is a nutritional metal required for brain development and function. Wilson's disease (WD), or hepatolenticular degeneration, is an inherited human copper metabolism disorder caused by a mutation of the ATP7B gene. Many WD patients present with variable neurological and psychiatric symptoms, which may be related to neurodegeneration secondary to copper metabolism imbalance. The objective of this study was to explore the feasibility and use of copper-64 chloride ([C]CuCl) as a tracer for noninvasive assessment of age-dependent changes of cerebral copper metabolism in WD using an Atp7b knockout mouse model of WD and positron emission tomography/computed tomography (PET/CT) imaging. Continuing from our recent study of biodistribution and radiation dosimetry of [C]CuCl in Atp7b knockout mice, PET quantitative analysis revealed low Cu radioactivity in the brains of Atp7b knockout mice at 7th weeks of age, compared with Cu radioactivity in the brains of age- and gender-matched wild type C57BL/6 mice, at 24 h (h) post intravenous injection of [C]CuCl as a tracer. Furthermore, age-dependent increase of Cu radioactivity was detected in the brains of Atp7b knockout mice from the 13th to 21th weeks of age, based on the data derived from a longitudinal [C]CuCl-PET/CT study of Atp7b knockout mice with orally administered [Cu]CuCl as a tracer. The findings of this study support clinical use of [Cu]CuCl-PET/CT imaging as a tool for noninvasive assessment of age-dependent changes of cerebral copper metabolism in WD patients presenting with variable neurological and psychiatric symptoms. [ABSTRACT FROM AUTHOR]

Aging is a risk factor for Alzheimer's disease (AD). There are changes of brain metabolism and biometal fluxes due to brain aging, which may play a role in pathogenesis of AD. Positron emission tomography (PET) is a versatile tool for tracking alteration of metabolism and biometal fluxes due to brain aging and AD. Age-dependent changes in cerebral glucose metabolism can be tracked with PET using 2-deoxy-2-[18F]-fluoro-D-glucose (18F-FDG), a radiolabeled glucose analogue, as a radiotracer. Based on different patterns of altered cerebral glucose metabolism, 18F-FDG PET was clinically used for differential diagnosis of AD and Frontotemporal dementia (FTD). There are continued efforts to develop additional radiopharmaceuticals or radiotracers for assessment of age-dependent changes of various metabolic pathways and biometal fluxes due to brain aging and AD with PET. Elucidation of age-dependent changes of brain metabolism and altered biometal fluxes is not only significant for a better mechanistic understanding of brain aging and the pathophysiology of AD, but also significant for identification of new targets for the prevention, early diagnosis, and treatment of AD. [ABSTRACT FROM AUTHOR]

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 (GABA A) receptor, amyloid-β, tau and receptor for advanced glycosylation end product (RAGE) can be detected in vivo in T2DM rats. Positron emission tomography (PET) using [18F]SDM-8 (SV2A), [18F]flumazenil (GABA A receptor), [18F]florbetapir (amyloid-β), [18F]PM-PBB3 (tau), and [18F]FPS-ZM1 (RAGE) was carried out in 12-month-old diabetic Zucker diabetic fatty (ZDF) and Sprague Dawley (SD) rats. Immunofluorescence staining, Thioflavin S staining, proteomic profiling and pathway analysis were performed on the brain tissues of ZDF and SD rats. 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 GABA A 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. These findings provide in vivo evidence for regional reductions in SV2A and GABA A receptor levels in the brains of aged T2DM ZDF rats. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: The nucleus basalis of Meynert (NBM) is known to play a crucial role in the development and pathogenesis of Alzheimer’s Disease (AD), particularly the cholinergic system within the NBM. However, the relationship between synaptic loss in the NBM and the clinical profile of AD remains unclear.In our study, we included 44 Aβ-negative normal controls (CN) and 76 Aβ-positive participants with cognitive impairment (CI). All participants underwent structural and diffusion magnetic resonance imaging (MRI), as well as positron emission tomography (PET) imaging to measure synaptic vesicle glycoprotein 2 A (SV2A) levels (Trial registration: NCT05623124. Registered 21 November 2022). The SV2A standardized uptake value ratios (SUVR) distribution in the NBM of CN participants was used as the reference norm. We investigated the association between NBM synaptic density and clinical performance, traditional AD biomarkers, and white matter tracts that passed the NBM.Participants with cognitive impairment (CI) who had NBM synaptic density below 1.5 standard deviations (SD) or 0.5 SD of the norm exhibited worse cognitive performance compared to cognitively normal (CN) individuals. Crucially, the extent of deviation in synaptic density from the norm was directly proportional to the severity of cognitive impairment and neurodegeneration biomarkers. Furthermore, among patients with cognitive impairment, synaptic loss in the NBM was associated with potential impairment in the density and organization of neurites within the white matter tracts connected to the NBM. Finally, neurite density index in the medial tracts may play a mediating role in the relationship between NBM synaptic density and MMSE scores.The extent that synaptic density in NBM deviated from the norm suggested the extent of worse cognitive performance and severe neurodegeneration. Furthermore, cognitive impairment associated with synaptic loss in the NBM may be mediated by its pathological impact on NBM white matter tracts.Methods: The nucleus basalis of Meynert (NBM) is known to play a crucial role in the development and pathogenesis of Alzheimer’s Disease (AD), particularly the cholinergic system within the NBM. However, the relationship between synaptic loss in the NBM and the clinical profile of AD remains unclear.In our study, we included 44 Aβ-negative normal controls (CN) and 76 Aβ-positive participants with cognitive impairment (CI). All participants underwent structural and diffusion magnetic resonance imaging (MRI), as well as positron emission tomography (PET) imaging to measure synaptic vesicle glycoprotein 2 A (SV2A) levels (Trial registration: NCT05623124. Registered 21 November 2022). The SV2A standardized uptake value ratios (SUVR) distribution in the NBM of CN participants was used as the reference norm. We investigated the association between NBM synaptic density and clinical performance, traditional AD biomarkers, and white matter tracts that passed the NBM.Participants with cognitive impairment (CI) who had NBM synaptic density below 1.5 standard deviations (SD) or 0.5 SD of the norm exhibited worse cognitive performance compared to cognitively normal (CN) individuals. Crucially, the extent of deviation in synaptic density from the norm was directly proportional to the severity of cognitive impairment and neurodegeneration biomarkers. Furthermore, among patients with cognitive impairment, synaptic loss in the NBM was associated with potential impairment in the density and organization of neurites within the white matter tracts connected to the NBM. Finally, neurite density index in the medial tracts may play a mediating role in the relationship between NBM synaptic density and MMSE scores.The extent that synaptic density in NBM deviated from the norm suggested the extent of worse cognitive performance and severe neurodegeneration. Furthermore, cognitive impairment associated with synaptic loss in the NBM may be mediated by its pathological impact on NBM white matter tracts.Results: The nucleus basalis of Meynert (NBM) is known to play a crucial role in the development and pathogenesis of Alzheimer’s Disease (AD), particularly the cholinergic system within the NBM. However, the relationship between synaptic loss in the NBM and the clinical profile of AD remains unclear.In our study, we included 44 Aβ-negative normal controls (CN) and 76 Aβ-positive participants with cognitive impairment (CI). All participants underwent structural and diffusion magnetic resonance imaging (MRI), as well as positron emission tomography (PET) imaging to measure synaptic vesicle glycoprotein 2 A (SV2A) levels (Trial registration: NCT05623124. Registered 21 November 2022). The SV2A standardized uptake value ratios (SUVR) distribution in the NBM of CN participants was used as the reference norm. We investigated the association between NBM synaptic density and clinical performance, traditional AD biomarkers, and white matter tracts that passed the NBM.Participants with cognitive impairment (CI) who had NBM synaptic density below 1.5 standard deviations (SD) or 0.5 SD of the norm exhibited worse cognitive performance compared to cognitively normal (CN) individuals. Crucially, the extent of deviation in synaptic density from the norm was directly proportional to the severity of cognitive impairment and neurodegeneration biomarkers. Furthermore, among patients with cognitive impairment, synaptic loss in the NBM was associated with potential impairment in the density and organization of neurites within the white matter tracts connected to the NBM. Finally, neurite density index in the medial tracts may play a mediating role in the relationship between NBM synaptic density and MMSE scores.The extent that synaptic density in NBM deviated from the norm suggested the extent of worse cognitive performance and severe neurodegeneration. Furthermore, cognitive impairment associated with synaptic loss in the NBM may be mediated by its pathological impact on NBM white matter tracts.Conclusion: The nucleus basalis of Meynert (NBM) is known to play a crucial role in the development and pathogenesis of Alzheimer’s Disease (AD), particularly the cholinergic system within the NBM. However, the relationship between synaptic loss in the NBM and the clinical profile of AD remains unclear.In our study, we included 44 Aβ-negative normal controls (CN) and 76 Aβ-positive participants with cognitive impairment (CI). All participants underwent structural and diffusion magnetic resonance imaging (MRI), as well as positron emission tomography (PET) imaging to measure synaptic vesicle glycoprotein 2 A (SV2A) levels (Trial registration: NCT05623124. Registered 21 November 2022). The SV2A standardized uptake value ratios (SUVR) distribution in the NBM of CN participants was used as the reference norm. We investigated the association between NBM synaptic density and clinical performance, traditional AD biomarkers, and white matter tracts that passed the NBM.Participants with cognitive impairment (CI) who had NBM synaptic density below 1.5 standard deviations (SD) or 0.5 SD of the norm exhibited worse cognitive performance compared to cognitively normal (CN) individuals. Crucially, the extent of deviation in synaptic density from the norm was directly proportional to the severity of cognitive impairment and neurodegeneration biomarkers. Furthermore, among patients with cognitive impairment, synaptic loss in the NBM was associated with potential impairment in the density and organization of neurites within the white matter tracts connected to the NBM. Finally, neurite density index in the medial tracts may play a mediating role in the relationship between NBM synaptic density and MMSE scores.The extent that synaptic density in NBM deviated from the norm suggested the extent of worse cognitive performance and severe neurodegeneration. Furthermore, cognitive impairment associated with synaptic loss in the NBM may be mediated by its pathological impact on NBM white matter tracts. [ABSTRACT FROM AUTHOR]

Reactive astrocytes play an important role in the development of Alzheimer's disease and primary tauopathies. Here, we aimed to investigate the relationships between reactive astrocytes. Microgliosis and glucose metabolism with Tau and amyloid beta pathology by using multi-tracer imaging in widely used tauopathy and familial Alzheimer's disease mouse models. Positron emission tomography imaging using [18F]PM-PBB3 (tau), [18F]florbetapir (amyloid-beta), [18F]SMBT-1 (monoamine oxidase-B), [18F]DPA-714 (translocator protein) and [18F]fluorodeoxyglucose was carried out in 3- and 7-month-old rTg4510 tau mice, 5 × FAD familial Alzheimer's disease mice and wild-type mice. Immunofluorescence staining was performed to validate the pathological distribution in the mouse brain after in vivo imaging. We found increased regional levels of [18F]PM-PBB3, [18F]SMBT-1, and [18F]DPA-714 and hypoglucose metabolism in the brains of 7-month-old rTg4510 mice compared to age-matched wild-type mice. Increased [18F]SMBT-1 uptake was observed in the brains of 3, 7-month-old 5 × FAD mice, with elevated regional [18F]florbetapir and [18F]DPA-714 uptakes in the brains of 7-month-old 5 × FAD mice, compared to age-matched wild-type mice. Positive correlations were shown between [18F]SMBT-1 and [18F]PM-PBB3, [18F]DPA-714 and [18F]PM-PBB3 in rTg4510 mice, and between [18F]florbetapir and [18F]DPA-714 SUVRs in 5 × FAD mice. In summary, these findings provide in vivo evidence that reactive astrocytes, microglial activation, and cerebral hypoglucose metabolism are associated with tau and amyloid pathology development in animal models of tauopathy and familial Alzheimer's disease. • Increased levels of [18F]SMBT-1 in the brains of 7-month-old rTg4510 mice compared to age-matched wild-type mice. • Higher [18F]SMBT-1 uptake in the brains of 3-, 7-month-old 5 × FAD mice compared to age-matched wild-type mice. • Positive correlations between the regional levels of [18F]SMBT-1 and [18F]DPA-714 in the brain of 5 × FAD mice. • Positive correlations between uptakes of [18F]SMBT-1 and [18F]PM-PBB3, and [18F]DPA-714 in the brain of rTg4510 mice. [ABSTRACT FROM AUTHOR]

• One-third refractory TLE subjects have a poor surgical prognosis. • Altered glucose metabolic brain network features in preoperative TLE subjects is related to surgical prognosis. • Elevated network integration and metabolic connectivity within contralateral occipitotemporal gyrus in preoperative TLE subjects is associated with ongoing postoperative seizures. • Redistributed hub nodes pattern with the midcingulate gyrus disappeared in preoperative TLE subjects is more amenable to obtaining poor prognosis. 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%