Brain Network and Abnormal Hemispheric Asymmetry Analyses to Explore the Marginal Differences in Glucose Metabolic Distributions Among Alzheimer's Disease, Parkinson's Disease Dementia, and Lewy Body Dementia

Facilitating accurate diagnosis and ensuring appropriate treatment of dementia subtypes, including Alzheimer's disease (AD), Parkinson's disease dementia (PDD), and Lewy body dementia (DLB), is clinically important. However, the differences in glucose metabolic distribution among these three dementia subtypes are minor, which can result in difficulties in diagnosis by visual assessment or traditional quantification methods. Here, we explored this issue using novel approaches, including brain network and abnormal hemispheric asymmetry analyses. We generated 18F-labeled fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) images from patients with AD, PDD, and DLB, and healthy control (HC) subjects (n = 22, 18, 22, and 22, respectively) from Huashan hospital, Shanghai, China. Brain network properties were measured and between-group differences evaluated using graph theory. We also calculated and explored asymmetry indices for the cerebral hemispheres in the four groups, to explore whether differences between the two hemispheres were characteristic of each group. Our study revealed significant differences in the network properties of the HC and AD groups (small-world coefficient, 1.36 vs. 1.28; clustering coefficient, 1.48 vs. 1.59; characteristic path length, 1.57 vs. 1.64). In addition, differing hub regions were identified in the different dementias. We also identified rightward asymmetry in the hemispheric brain networks of patients with AD and DLB, and leftward asymmetry in the hemispheric brain networks of patients with PDD, which were attributable to aberrant topological properties in the corresponding hemispheres

Frequency-Dependent Relationship Between Resting-State fMRI and Glucose Metabolism in the Elderly

Both glucose metabolism and resting-state fMRI (RS-fMRI) signal reflect hemodynamic features. The objective of this study was to investigate their relationship in the resting-state in healthy elderly participants (n = 18). For RS-fMRI signal, regional homogeneity (ReHo), amplitude of low frequency fluctuations (ALFF), fractional ALFF (fALFF), and degree of centrality (DC) maps were generated in multiple frequency bands. Glucose uptake was acquired with 18F-fluorodeoxyglucose positron emission tomography (FDG-PET). Linear correlation of each pair of the FDG-PET and RS-fMRI metrics was explored both in across-voxel way and in across-subject way. We found a significant across-voxel correlation between the FDG-PET and BOLD-fMRI metrics. However, only a small portion of voxels showed significant across-subject correlation between FDG-PET and BOLD-fMRI metrics. All these results were similar across all frequency bands of RS-fMRI data. The current findings indicate that FDG-PET and RS-fMRI metrics share similar spatial pattern (significant across-voxel correlation) but have different underlying physiological importance (non-significant across-subject correlation). Specifically, FDG-PET measures the mean glucose metabolism over tens of minutes, while RS-fMRI measures the dynamic characteristics. The combination of FDG-PET and RS-fMRI provides complementary information to reveal the underlying mechanisms of the brain activity and may enable more comprehensive interpretation of clinical PET-fMRI studies. Future studies would attempt to reduce the artifacts of RS-fMRI and to analyze the dynamic feature of PET signal

Reduced SV2A and GABAA_A receptor levels in the brains of type 2 diabetic rats revealed by [18^{18}F]SDM-8 and [18^{18}F]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 (GABA$_A$) receptor, amyloid-β, tau and receptor for advanced glycosylation end product (RAGE) can be detected in vivo in T2DM rats. Methods: Positron emission tomography (PET) using [$^{18}$F]SDM-8 (SV2A), [$^{18}$F]flumazenil (GABA$_A$ receptor), [$^{18}$F]florbetapir (amyloid-β), [$^{18}$F]PM-PBB3 (tau), and [$^{18}$F]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 [$^{18}$F]SDM-8 uptake and cortical and hippocampal [$^{18}$F]flumazenil uptake were observed in 12-month-old ZDF rats compared to SD rats. The regional uptake of [$^{18}$F]florbetapir and [$^{18}$F]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. Conclusion: These findings provide in vivo evidence for regional reductions in SV2A and GABA$_A$ receptor levels in the brains of aged T2DM ZDF rats

In vivo reactive astrocyte imaging using 18FSMBT-1 in tauopathy and familial Alzheimer’s disease mouse models: A multi-tracer study

Background: 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. Results: Positron emission tomography imaging using 18FPM-PBB3 (tau), 18Fflorbetapir (amyloid-beta), 18FSMBT-1 (monoamine oxidase-B), 18FDPA-714 (translocator protein) and 18Ffluorodeoxyglucose 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 18FPM-PBB3, 18FSMBT-1, and 18FDPA-714 and hypoglucose metabolism in the brains of 7-month-old rTg4510 mice compared to age-matched wild-type mice. Increased 18FSMBT-1 uptake was observed in the brains of 3, 7-month-old 5 × FAD mice, with elevated regional 18Fflorbetapir and 18FDPA-714 uptakes in the brains of 7-month-old 5 × FAD mice, compared to age-matched wild-type mice. Positive correlations were shown between 18FSMBT-1 and 18FPM-PBB3, 18FDPA-714 and 18FPM-PBB3 in rTg4510 mice, and between 18Fflorbetapir and 18FDPA-714 SUVRs in 5 × FAD mice. Conclusion: 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

Associations of [18F]-APN-1607 Tau PET Binding in the Brain of Alzheimer's Disease Patients With Cognition and Glucose Metabolism.

Molecular imaging of tauopathies is complicated by the differing specificities and off-target binding properties of available radioligands for positron emission tomography (PET). [18F]-APN-1607 ([18F]-PM-PBB3) is a newly developed PET tracer with promising properties for tau imaging. We aimed to characterize the cerebral binding of [18F]-APN-1607 in Alzheimer's disease (AD) patients compared to normal control (NC) subjects. Therefore, we obtained static late frame PET recordings with [18F]-APN-1607 and [18F]-FDG in patients with a clinical diagnosis of AD group, along with an age-matched NC group ([18F]-APN-1607 only). Using statistical parametric mapping (SPM) and volume of interest (VOI) analyses of the reference region normalized standardized uptake value ratio maps, we then tested for group differences and relationships between both PET biomarkers, as well as their associations with clinical general cognition. In the AD group, [18F]-APN-1607 binding was elevated in widespread cortical regions (P < 0.001 for VOI analysis, familywise error-corrected P < 0.01 for SPM analysis). The regional uptake in AD patients correlated negatively with Mini-Mental State Examination score (frontal lobe: R = -0.632, P = 0.004; temporal lobe: R = -0.593, P = 0.008; parietal lobe: R = -0.552, P = 0.014; insula: R = -0.650, P = 0.003; cingulum: R = -0.665, P = 0.002) except occipital lobe (R = -0.417, P = 0.076). The hypometabolism to [18F]-FDG PET in AD patients also showed negative correlations with regional [18F]-APN-1607 binding in some signature areas of AD (temporal lobe: R = -0.530, P = 0.020; parietal lobe: R = -0.637, P = 0.003; occipital lobe: R = -0.567, P = 0.011). In conclusion, our results suggested that [18F]-APN-1607 PET sensitively detected tau deposition in AD and that individual tauopathy correlated with impaired cerebral glucose metabolism and cognitive function

Increased Vesicular Monoamine Transporter 2 (VMAT2) and Dopamine Transporter (DAT) Expression in Adolescent Brain Development: A Longitudinal Micro-PET/CT Study in Rodent

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

Relationship Between Reactive Astrocytes, by [18F]SMBT-1 Imaging, with Amyloid-Beta, Tau, Glucose Metabolism, and TSPO in Mouse Models of Alzheimer’s Disease

Reactive astrocytes play an important role in the development of Alzheimer’s disease (AD). Here, we aimed to investigate the temporospatial relationships among monoamine oxidase-B, tau and amyloid-β (Aβ), translocator protein, and glucose metabolism by using multitracer imaging in AD transgenic mouse models. Positron emission tomography (PET) imaging with [18F]SMBT-1 (monoamine oxidase-B), [18F]florbetapir (Aβ), [18F]PM-PBB3 (tau), [18F]fluorodeoxyglucose (FDG), and [18F]DPA-714 (translocator protein) was carried out in 5- and 10-month-old APP/PS1, 11-month-old 3×Tg mice, and aged-matched wild-type mice. The brain regional referenced standard uptake value (SUVR) was computed with the cerebellum as the reference region. Immunofluorescence staining was performed on mouse brain tissue slices. [18F]SMBT-1 and [18F]florbetapir SUVRs were greater in the cortex and hippocampus of 10-month-old APP/PS1 mice than in those of 5-month-old APP/PS1 mice and wild-type mice. No significant difference in the regional [18F]FDG or [18F]DPA-714 SUVRs was observed in the brains of 5- or 10-month-old APP/PS1 mice or wild-type mice. No significant difference in the SUVRs of any tracer was observed between 11-month-old 3×Tg mice and age-matched wild-type mice. A positive correlation between the SUVRs of [18F]florbetapir and [18F]DPA-714 in the cortex and hippocampus was observed among the transgenic mice. Immunostaining validated the distribution of MAO-B and limited Aβ and tau pathology in 11-month-old 3×Tg mice; and Aβ deposits in brain tissue from 10-month-old APP/PS1 mice. In summary, these findings provide in vivo evidence that an increase in astrocyte [18F]SMBT-1 accompanies Aβ accumulation in APP/PS1 models of AD amyloidosis

Parametric Estimation of Reference Signal Intensity for Semi-Quantification of Tau Deposition: A Flortaucipir and [18F]-APN-1607 Study

BackgroundTau positron emission tomography (PET) imaging can reveal the pathophysiology and neurodegeneration that occurs in Alzheimer’s disease (AD) in vivo. The standardized uptake value ratio (SUVR) is widely used for semi-quantification of tau deposition but is susceptible to disturbance from the reference region and the partial volume effect (PVE). To overcome this problem, we applied the parametric estimation of reference signal intensity (PERSI) method—which was previously evaluated for flortaucipir imaging—to two tau tracers, flortaucipir and [18F]-APN-1607.MethodsTwo cohorts underwent tau PET scanning. Flortaucipir PET imaging data for cohort I (65 healthy controls [HCs], 60 patients with mild cognitive impairment [MCI], and 12 AD patients) were from the AD Neuroimaging Initiative database. [18F]-APN-1607 ([18F]-PM-PBB3) PET imaging data were for Cohort II, which included 21 patients with a clinical diagnosis of amyloid PET-positive AD and 15 HCs recruited at Huashan Hospital. We used white matter (WM) postprocessed by PERSI (PERSI-WM) as the reference region and compared this with the traditional semi-quantification method that uses the whole cerebellum as the reference. SUVRs were calculated for regions of interest including the frontal, parietal, temporal, and occipital lobes; anterior and posterior cingulate; precuneus; and Braak I/II (entorhinal cortex and hippocampus). Receiver operating characteristic (ROC) curve analysis and effect sizes were used to compare the two methods in terms of ability to discriminate between different clinical groups.ResultsIn both cohorts, regional SUVR determined using the PERSI-WM method was superior to using the cerebellum as reference region for measuring tau retention in AD patients (e.g., SUVR of the temporal lobe: flortaucipir, 1.08 ± 0.17 and [18F]-APN-1607, 1.57 ± 0.34); and estimates of the effect size and areas under the ROC curve (AUC) indicated that it also increased between-group differences (e.g., AUC of the temporal lobe for HC vs AD: flortaucipir, 0.893 and [18F]-APN-1607: 0.949).ConclusionThe PERSI-WM method significantly improves diagnostic discrimination compared to conventional approach of using the cerebellum as a reference region and can mitigate the PVE; it can thus enhance the efficacy of semi-quantification of multiple tau tracers in PET scanning, making it suitable for large-scale clinical application