Towards multicenter ß-amyloid PET imaging in mouse models: A triple scanner head-to-head comparison.

AIM: ß-amyloid (Aß) small animal PET facilitates quantification of fibrillar amyloidosis in Alzheimer's disease (AD) mouse models. Thus, the methodology is receiving growing interest as a monitoring tool in preclinical drug trials. In this regard, harmonization of data from different scanners at multiple sites would allow the establishment large collaborative cohorts and may facilitate efficacy comparison of different treatments. Therefore, we objected to determine the level of agreement of Aß-PET quantification by a head-to-head comparison of three different state-of-the-art small animal PET scanners, which could help pave the way for future multicenter studies. METHODS: Within a timeframe of 5 ± 2 weeks, transgenic APPPS1 (n = 9) and wild-type (WT) (n = 8) mice (age range: 13-16 months) were examined three times by Aß-PET ([18F]florbetaben) using a Siemens Inveon DPET, a MedisonanoScan PET/MR, and a MedisonanoScan PET/CT with harmonized reconstruction protocols. Cortex-to-white-matter 30-60 min p.i. standardized uptake value ratios (SUVRCTX/WM) were calculated to compare binding differences, effect sizes (Cohen's d) and z-score values of APPPS1 relative to WT mice. Correlation coefficients (Pearson's r) were calculated for the agreement of individual SUVR between different scanners. Voxel-wise analysis was used to determine the agreement of spatial pathology patterns. For validation of PET imaging against the histological gold standard, individual SUVR values were subject to a correlation analysis with area occupancy of methoxy­X04 staining. RESULTS: All three small animal PET scanners yielded comparable group differences between APPPS1 and WT mice (∆PET=20.4 % ± 2.9 %, ∆PET/MR=18.4 % ± 4.5 %, ∆PET/CT=18.1 % ± 3.3 %). Voxel-wise analysis confirmed a high degree of congruency of the spatial pattern (Dice coefficient (DC)PETvs.PET/MR=83.0 %, DCPETvs.PET/CT=69.3 %, DCPET/MRvs.PET/CT=81.9 %). Differences in the group level variance of the three scanners resulted in divergent z-scores (zPET=11.5 ± 1.6; zPET/MR=5.3 ± 1.3; zPET/CT=3.4 ± 0.6) and effect sizes (dPET=8.5, dPET/MR=4.5, dPET/CT=4.1). However, correlations at the individual mouse level were still strong between scanners (rPETvs.PET/MR=0.96, rPETvs.PET/CT=0.91, rPET/MRvs.PET/CT=0.87; all p ≤ 0.0001). Methoxy-X04 staining exhibited a significant correlation across all three PET machines combined (r = 0.76, p < 0.0001) but also at individual level (PET: r = 0.81, p = 0.026; PET/MR: r = 0.89, p = 0.0074; PET/CT: r = 0.93, p = 0.0028). CONCLUSIONS: Our comparison of standardized small animal Aß-PET acquired by three different scanners substantiates the possibility of moving towards a multicentric approach in preclinical AD research. The alignment of image acquisition and analysis methods achieved good overall comparability between data sets. Nevertheless, differences in variance of sensitivity and specificity of different scanners may limit data interpretation at the individual mouse level and deserves methodological optimization.

The application of a multidisciplinary approach in the diagnosis of Castleman disease and Castleman-like lymphadenopathies: A 20-year retrospective analysis of clinical and pathological features.

BACKGROUND: Castleman disease (CD) comprises a group of rare and heterogeneous haematological disorders, including unicentric (UCD) and multicentric (MCD) forms, the latter further subdivided into HHV8-MCD, POEMS-MCD and idiopathic-MCD (iMCD). However, according to the Castleman Disease Collaborative Network guidelines, the diagnosis of CD can only be achieved through collaboration between clinicians and pathologists. METHODS: We applied these clinical and pathological criteria and implement with clonality testing to a retrospective cohort of 48 adult and paediatric Italian patients diagnosed with reactive lymphadenitis with CD-like histological features. RESULTS: We confirmed the diagnosis of CD in 60% (29/48) of the cases, including 12 (41%) UCD and 17 (59%; five HHV8-MCD, three POEMS-MCD and nine iMCD) MCD. Of the remaining 19 cases (40%) with multiple lymphadenopathy, 5 (26%) were classified as autoimmune diseases, 1 (5%) as autoimmune lymphoproliferative disorder, 1 (5%) as IgG4-related disease, 11 (83%) as reactive lymphadenitis and 1 (5%) as nodal marginal zone lymphoma. CONCLUSIONS: Our study emphasizes the importance of the multidisciplinary approach to reactive lymphadenitis with CD-like features in order to achieve a definitive diagnosis and choose the appropriate treatment.

Proliferation and apoptosis after whole-body irradiation: longitudinal PET study in a mouse model.

PURPOSE: A reliable method for regional in vivo imaging of radiation-induced cellular damage would be of great importance for the detection of therapy-induced injury to healthy tissue and the choice of adequate treatment of radiation emergency patients in both civilian and military events. This study aimed to investigate in a mouse model if positron emission tomography (PET) imaging with proliferation and apoptosis markers is potentially suitable for this purpose. METHODS: Four groups, including twenty mice (wild-type C57BL/6) each, were whole-body irradiated with 0 Gy, 0.5 Gy, 1 Gy, and 3 Gy and examined by PET over a six-month period at defined time points. 3'-[18F]fluoro-3'-deoxythymidine ([18F]FLT) and 2-(5-[18F]fluoropentyl)-2-methyl malonic acid ([18F]ML-10) were used to visualise proliferation and apoptosis. Regional standard uptake values were compared with respect to irradiation dose over time. Histologic data and peripheral blood cell values were correlated with the PET results. RESULTS: The hematopoietic bone marrow showed a significantly increased [18F]FLT signal at early time points after radiation exposure (day 3 and day 7). This correlated with blood parameters, especially leukocytes, and histological data. A significantly increased [18F]FLT signal also occurred in the gastrointestinal tract and thymus at early time points. An increased [18F]ML-10 signal related to irradiation doses was observed in the bone marrow on day 8, but there was a high variability of standard uptake values and no correlation with histological data. CONCLUSION: [18F]FLT showed potential to visualise the extent, regional distribution and recovery from radiation-induced cellular damage in the bone marrow, gastrointestinal tract and thymus. The potential of [18F]FLT imaging to assess the extent of bone marrow affected by irradiation might be especially useful to predict the subsequent severity of hematopoietic impairment and to adapt the therapy of the bone marrow reserve. [18F]ML-10 PET proved to be not sensitive enough for the reliable detection of radiation induced apoptosis.

The Spectrum of Neurological and Sensory Abnormalities in Gaucher Disease Patients: A Multidisciplinary Study (SENOPRO).

Gaucher disease (GD) has been increasingly recognized as a continuum of phenotypes with variable neurological and sensory involvement. No study has yet specifically explored the spectrum of neuropsychiatric and sensory abnormalities in GD patients through a multidisciplinary approach. Abnormalities involving the nervous system, including sensory abnormalities, cognitive disturbances, and psychiatric comorbidities, have been identified in GD1 and GD3 patients. In this prospective study, named SENOPRO, we performed neurological, neuroradiological, neuropsychological, ophthalmological, and hearing assessments in 22 GD patients: 19 GD1 and 3 GD3. First, we highlighted a high rate of parkinsonian motor and non-motor symptoms (including high rates of excessive daytime sleepiness), especially in GD1 patients harboring severe glucocerebrosidase variants. Secondly, neuropsychological evaluations revealed a high prevalence of cognitive impairment and psychiatric disturbances, both in patients initially classified as GD1 and GD3. Thirdly, hippocampal brain volume reduction was associated with impaired short- and long-term performance in an episodic memory test. Fourthly, audiometric assessment showed an impaired speech perception in noise in the majority of patients, indicative of an impaired central processing of hearing, associated with high rates of slight hearing loss both in GD1 and GD3 patients. Finally, relevant structural and functional abnormalities along the visual system were found both in GD1 and GD3 patients by means of visual evoked potentials and optical coherence tomography. Overall, our findings support the concept of GD as a spectrum of disease subtypes, and support the importance of in-depth periodic monitoring of cognitive and motor performances, mood, sleep patterns, and sensory abnormalities in all patients with GD, independently from the patient's initial classification.

Are heterobivalent GRPR- and VPAC1R-bispecific radiopeptides suitable for efficient in vivo tumor imaging of prostate carcinomas?

Receptor-specific peptides labeled with positron emitters play an important role in the clinical imaging of several malignancies by positron emission tomography (PET). Radiolabeled heterobivalent bispecific peptidic ligands (HBPLs) can target more than one receptor type and by this - besides exhibiting other advantages - increase tumor imaging sensitivity. In the present study, we show the initial in vivo evaluation of the most potent heterobivalent gastrin-releasing peptide receptor (GRPR)- and vasoactive intestinal peptide receptor subtype 1 (VPAC1R)-bispecific radiotracer and determined its tumor visualization potential via PET/CT imaging. For this purpose, the most potent described HBPL was synthesized together with its partly scrambled heterobivalent monospecific homologs and its monovalent counterparts. The agents were efficiently labeled with 68Ga3+ and evaluated in an initial PET/CT tumor imaging study in a human prostate carcinoma (PCa) xenograft rat tumor model established for this purpose. None of the three 68Ga-HBPLs enabled a clear tumor visualization and a considerably higher involvement in receptor-mediated uptake was found for the GRPR-binding part of the molecule than for the VPAC1R-binding one. Of the monovalent radiotracers, only [68Ga]Ga-NODA-GA-PESIN could efficiently delineate the tumor, confirming the results. Thus, this work sets the direction for future developments in the field of GRPR- and VPAC1R-bispecific radioligands, which should be based on other VPAC1R-specific peptides than PACAP-27.

Gaucher Disease and Myelofibrosis: A Combined Disease or a Misdiagnosis?

BACKGROUND: Gaucher disease (GD) and primary myelofibrosis (PMF) share similar clinical and laboratory features, such as cytopenia, hepatosplenomegaly, and marrow fibrosis, often resulting in a misdiagnosis. CASE REPORT: We report here the case of a young woman with hepatosplenomegaly, leukopenia, and thrombocytopenia. Based on bone marrow (BM) findings and on liver biopsy showing extramedullary hematopoiesis, an initial diagnosis of PMF was formulated. The patient refused stem cell transplantation from an HLA-identical sibling. Low-dose melphalan was given, without any improvement. Two years later, a BM evaluation showed Gaucher cells. Low glucocerebrosidase and high chitotriosidase levels were indicative for GD. Molecular analysis revealed N370S/complex I mutations. Enzyme replacement therapy with imiglucerase was commenced, resulting in clinical and hematological improvements. Due to an unexpected and persistent organomegaly, PMF combined with GD were suspected. JAK2V617F, JAK2 exon 12, MPL, calreticulin, and exon 9 mutations were negative, and BM examination showed no marrow fibrosis. PMF was excluded. Twenty years after starting treatment, the peripheral cell count and liver size were normal, whereas splenomegaly persisted. CONCLUSION: In order to avoid a misdiagnosis, a diagnostic algorithm for patients with hepatosplenomegaly combined with cytopenia is suggested.

Liquefied Petroleum Gas Monitoring System Based on Polystyrene Coated Long Period Grating.

In this work, we report the in-field demonstration of a liquefied petroleum gas monitoring system based on optical fiber technology. Long-period grating coated with a thin layer of atactic polystyrene (aPS) was employed as a gas sensor, and an array comprising two different fiber Bragg gratings was set for the monitoring of environmental conditions such as temperature and humidity. A custom package was developed for the sensors, ensuring their suitable installation and operation in harsh conditions. The developed system was installed in a real railway location scenario (i.e., a southern Italian operative railway tunnel), and tests were performed to validate the system performances in operational mode. Daytime normal working operations of the railway line and controlled gas expositions, at very low concentrations, were the searched realistic conditions for an out-of-lab validation of the developed system. Encouraging results were obtained with a precise indication of the gas concentration and external conditioning of the sensor.

Thrombocythemia and polycythemia in patients younger than 20 years at diagnosis: clinical and biologic features, treatment, and long-term outcome.

Sixty-four patients < 20 years of age, investigated for a suspicion of Philadelphia-negative myeloproliferative disease (MPD), were retrospectively evaluated to characterize the different forms and to examine the treatments used and long-term outcome. JAK2 mutations, endogenous erythroid colony growth, and clonality were investigated in 51 children. Mutations of thrombopoietin, the thrombopoietin receptor (MPL), and the erythropoietin receptor and mutations of other genes involved in the pathogenesis of MPD were investigated in JAK2 wild-type patients. Based on our criteria for childhood MPD, we identified 34 patients with sporadic thrombocythemia (ST), 16 with hereditary thrombocytosis (HT), 11 with sporadic polycythemia (SP), and 3 with hereditary polycythemia (HP). JAK2(V617F) mutations were present in 47.5% of ST and in no HT. The MPL(S505A) mutation was detected in 15/16 HT patients and in no ST (P < .00001). The JAK2(V617F) mutation occurred in 27% of SP patients diagnosed according to the Polycythemia Vera Study Group or World Health Organization 2001 criteria. Children with ST received more cytoreductive drugs than those with HT (P = .0006). After a median follow-up of 124 months, no patient had developed leukemia or myelofibrosis and 5% had thrombosis; the miscarriage rate in thrombocythemic patients was 14%. The low complication rate in our population suggests that children with MPD may be managed by tailored approaches.

Development and Preclinical Evaluation of a Copper-64-Labeled Antibody Targeting Glycine-Alanine Dipeptides for PET Imaging of C9orf72-Associated Amyotrophic Lateral Sclerosis/Frontotemporal Dementia.

Aggregating poly(glycine-alanine) (poly-GA) is derived from the unconventional translation of the pathogenic intronic hexanucleotide repeat expansion in the C9orf72 gene, which is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Poly-GA accumulates predominantly in neuronal cytoplasmic inclusions unique to C9orf72 ALS/FTD patients. Poly-GA is, therefore, a promising target for PET/CT imaging of FTD/ALS to monitor disease progression and therapeutic interventions. A novel 64Cu-labeled anti-GA antibody (mAb1A12) targeting the poly-GA protein was developed and evaluated in a transgenic mouse model. It was obtained with high radiochemical purity (RCP), radiochemical yield (RCY), and specific activity, and showed high stability in vitro and ex vivo and specifically bound to poly-GA. The affinity of NODAGA-mAb1A12 for poly-GA was not affected by this modification. [64Cu]Cu-NODAGA-mAb1A12 was injected into transgenic mice expressing GFP-(GA)175 in excitatory neurons driven by Camk2a-Cre and in control littermates. PET/CT imaging was performed at 2, 20, and 40 h post-injection (p.i.) and revealed a higher accumulation in the cortex in transgenic mice than in wild-type mice, as reflected by higher standardized uptake value ratios (SUVR) using the cerebellum as the reference region. The organs were isolated for biodistribution and ex vivo autoradiography. Autoradiography revealed a higher cortex-to-cerebellum ratio in the transgenic mice than in the controls. Results from autoradiography were validated by immunohistochemistry and poly-GA immunoassays. Moreover, we confirmed antibody uptake in the CNS in a pharmacokinetic study of the perfused tissues. In summary, [64Cu]Cu-NODAGA-mAb1A12 demonstrated favorable in vitro characteristics and an increased relative binding in poly-GA transgenic mice compared to wild-type mice in vivo. Our results with this first-in-class radiotracer suggested that targeting poly-GA is a promising approach for PET/CT imaging in FTD/ALS.

Urinary sFlt-1 and PlGF as preeclampsia predictors: sFlt-1/creatinine ratio improves the prediction value.

OBJECTIVES: To evaluate the correlation between maternal serum and urinary soluble Fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) levels and to assess their potential value in preeclampsia and fetal growth restriction. STUDY DESIGN: This case-control longitudinal prospective study was performed in 49 singleton pregnant women, divided into two clinical groups, low risk pregnancy (n = 23) and pregnancy complicated by preeclampsia (n = 26). Maternal serum and urinary sFlt-1 and PlGF levels were quantified by electrochemiluminescence. Every patient underwent an ultrasound for fetal biometry. Doppler assessment was done when estimated fetal weight was under the 10th centile. ROC curves were used to evaluate the predictive capability of serum and urinary angiogenic biomarkers and their ratios on preeclampsia. Linear regression was used to compare the values of serum and urinary sFlt-1 and PlGF and their ratios. RESULTS: Urine biomarkers were positively associated with their serum values, being the best associated urinary PlGF (R2 = 0.73), which also showed the highest predictive capability of preeclampsia of urine biomarkers (AUC 0.866). The predictive capability of urinary sFlt-1 was much lower (AUC 0.640), but increased when adjusting by serum creatinine, a more precise parameter (AUC 0.863). CONCLUSIONS: Urinary PlGF could be a lesser invasive alternative to circulating biomarkers to monitor pregnancies complicated with preeclampsia that need repeated controls of their pregnancy complication. Urinary sFlt-1 values need adjustment by serum creatinine to be reliable.

Real-practice management and treatment of idiopathic multicentric Castleman disease with siltuximab: a collection of clinical experiences.

Castleman disease (CD) is a group of lymphoproliferative disorders that share common histopathological features yet have widely different aetiologies, clinical features and grades of severity as well as treatments and outcomes. Siltuximab is currently the only therapy approved by the FDA and EMA for idiopathic multicentric CD and is recommended as first-line therapy in treatment guidelines. Despite the extensive characterization of siltuximab treatment in clinical trials, available evidence from real-world practice is still scant. This collection of clinical experiences focuses on patients treated with siltuximab therapy, particularly regarding the idiopathic multicentric CD diagnostic work-up, and on treatment administration in patients with complex disease entering differential diagnosis with CD or concomitant diseases. Thus, these data help further characterize and improve the use of siltuximab in real practice in terms of effectiveness and safety of long-term administration as well as consequences of treatment interruption.

PET imaging of microglia in Alzheimer's disease using copper-64 labeled TREM2 antibodies.

Triggering receptor expressed on myeloid cells 2 (TREM2) plays an essential role in microglia activation and is being investigated as a potential therapeutic target for modulation of microglia in several neurological diseases. In this study, we present the development and preclinical evaluation of 64Cu-labeled antibody-based PET radiotracers as tools for non-invasive assessment of TREM2 expression. Furthermore, we tested the potential of an antibody transport vehicle (ATV) that binds human transferrin receptor to facilitate transcytosis of TREM2 antibody-based radiotracers to the CNS and improve target engagement. Methods: A TREM2 antibody with an engineered transport vehicle (ATV:4D9) and without (4D9) were covalently modified with pNCS-benzyl-NODAGA and labeled with copper-64. Potency, stability, and specificity were assessed in vitro followed by in vivo PET imaging at the early 2 h, intermediate 20 h, and late imaging time points 40 h post-injection using a human transferrin receptor (hTfR) expressing model for amyloidogenesis (5xFAD;TfRmu/hu) or wild-type mice (WT;TfRmu/hu), and hTfR negative controls. Organs of interest were isolated to determine biodistribution by ex vivo autoradiography. Cell sorting after in vivo tracer injection was used to demonstrate cellular specificity for microglia and to validate TREM2 PET results in an independent mouse model for amyloidogenesis (AppSAA;TfRmu/hu). For translation to human imaging, a human TREM2 antibody (14D3) was radiolabeled and used for in vitro autoradiography on human brain sections. Results: The 64Cu-labeled antibodies were obtained in high radiochemical purity (RCP), radiochemical yield (RCY), and specific activity. Antibody modification did not impact TREM2 binding. ATV:4D9 binding proved to be specific, and the tracer stability was maintained over 48 h. The uptake of [64Cu]Cu-NODAGA-ATV:4D9 in the brains of hTfR expressing mice was up to 4.6-fold higher than [64Cu]Cu-NODAGA-4D9 in mice without hTfR. TREM2 PET revealed elevated uptake in the cortex of 5xFAD mice compared to wild-type, which was validated by autoradiography. PET-to-biodistribution correlation revealed that elevated radiotracer uptake in brains of 5xFAD;TfRmu/hu mice was driven by microglia-rich cortical and hippocampal brain regions. Radiolabeled ATV:4D9 was selectively enriched in microglia and cellular uptake explained PET signal enhancement in AppSAA;TfRmu/hu mice. Human autoradiography showed elevated TREM2 tracer binding in the cortex of patients with Alzheimer's disease. Conclusion: [64Cu]Cu-NODAGA-ATV:4D9 has potential for non-invasive assessment of TREM2 as a surrogate marker for microglia activation in vivo. ATV engineering for hTfR binding and transcytosis overcomes the blood-brain barrier restriction for antibody-based PET radiotracers. TREM2 PET might be a versatile tool for many applications beyond Alzheimer's disease, such as glioma and chronic inflammatory diseases.

MUNDUS project: MUltimodal neuroprosthesis for daily upper limb support.

BACKGROUND: MUNDUS is an assistive framework for recovering direct interaction capability of severely motor impaired people based on arm reaching and hand functions. It aims at achieving personalization, modularity and maximization of the user's direct involvement in assistive systems. To this, MUNDUS exploits any residual control of the end-user and can be adapted to the level of severity or to the progression of the disease allowing the user to voluntarily interact with the environment. MUNDUS target pathologies are high-level spinal cord injury (SCI) and neurodegenerative and genetic neuromuscular diseases, such as amyotrophic lateral sclerosis, Friedreich ataxia, and multiple sclerosis (MS). The system can be alternatively driven by residual voluntary muscular activation, head/eye motion, and brain signals. MUNDUS modularly combines an antigravity lightweight and non-cumbersome exoskeleton, closed-loop controlled Neuromuscular Electrical Stimulation for arm and hand motion, and potentially a motorized hand orthosis, for grasping interactive objects. METHODS: The definition of the requirements and of the interaction tasks were designed by a focus group with experts and a questionnaire with 36 potential end-users. RESULTS: The functionality of all modules has been successfully demonstrated. User's intention was detected with a 100% success. Averaging all subjects and tasks, the minimum evaluation score obtained was 1.13 ± 0.99 for the release of the handle during the drinking task, whilst all the other sub-actions achieved a mean value above 1.6. All users, but one, subjectively perceived the usefulness of the assistance and could easily control the system. Donning time ranged from 6 to 65 minutes, scaled on the configuration complexity. CONCLUSIONS: The MUNDUS platform provides functional assistance to daily life activities; the modules integration depends on the user's need, the functionality of the system have been demonstrated for all the possible configurations, and preliminary assessment of usability and acceptance is promising.

Longitudinal Studies on Alzheimer Disease Mouse Models with Multiple Tracer PET/CT: Application of Reduction and Refinement Principles in Daily Practice to Safeguard Animal Welfare during Progressive Aging.

Longitudinal studies on mouse models related to Alzheimer disease (AD) pathology play an important role in the investigation of therapeutic targets to help pharmaceutical research in the development of new drugs and in the attempt of an early diagnosis that can contribute to improving people's quality of life. There are several advantages to enriching longitudinal studies in AD models with Positron Emission Tomography (PET); among these advantages, the possibility of following the principle of the 3Rs of animal welfare is fundamental. In this manuscript, good daily experimental practice focusing on animal welfare is described and commented upon, based on the experience attained from studies conducted in our Nuclear Medicine department.

Ropeginterferon alfa-2b treatment in a young patient with multi-refractory polycythemia vera and double JAK2 gene mutation: a case report.

This case report presents a 3-year-old female patient initially diagnosed with polycythemia vera (PV) in 2001. The patient exhibited elevated red blood cell (RBC) counts, high hemoglobin (Hb) levels, hyperleukocytosis, and moderate thrombocytosis, with sporadic abdominal pain and significant splenomegaly. Despite various treatments, including phlebotomies, hydroxyurea, and alpha-interferon, the patient struggled to maintain optimal hematocrit levels and experienced persistent symptoms. Subsequent genomic analysis revealed a rare JAK2 G301R mutation alongside the canonical JAK2 V617F mutation, potentially contributing to disease severity. In 2023, the patient started Ropeginterferon alfa-2b, leading to improved hematological parameters and symptom relief. The case underscores the challenges in managing PV, particularly in young patients, and highlights the potential clinical significance of additional JAK2 mutations/variants and the potential benefits of Ropeginterferon alfa-2b in achieving better disease control.

Longitudinal [18]UCB-H/[18F]FDG imaging depicts complex patterns of structural and functional neuroplasticity following bilateral vestibular loss in the rat.

Neuronal lesions trigger mechanisms of structural and functional neuroplasticity, which can support recovery. However, the temporal and spatial appearance of structure-function changes and their interrelation remain unclear. The current study aimed to directly compare serial whole-brain in vivo measurements of functional plasticity (by [18F]FDG-PET) and structural synaptic plasticity (by [18F]UCB-H-PET) before and after bilateral labyrinthectomy in rats and investigate the effect of locomotor training. Complex structure-function changes were found after bilateral labyrinthectomy: in brainstem-cerebellar circuits, regional cerebral glucose metabolism (rCGM) decreased early, followed by reduced synaptic density. In the thalamus, increased [18F]UCB-H binding preceded a higher rCGM uptake. In frontal-basal ganglia loops, an increase in synaptic density was paralleled by a decrease in rCGM. In the group with locomotor training, thalamic rCGM and [18F]UCB-H binding increased following bilateral labyrinthectomy compared to the no training group. Rats with training had considerably fewer body rotations. In conclusion, combined [18F]FDG/[18F]UCB-H dual tracer imaging reveals that adaptive neuroplasticity after bilateral vestibular loss is not a uniform process but is composed of complex spatial and temporal patterns of structure-function coupling in networks for vestibular, multisensory, and motor control, which can be modulated by early physical training.