396 results found
Erritzoe D, Godlewska BR, Rizzo G, et al., 2023, Brain Serotonin Release Is Reduced in Patients With Depression: A [11C]Cimbi-36 Positron Emission Tomography Study With a d-Amphetamine Challenge., Biol Psychiatry, Vol: 93, Pages: 1089-1098
BACKGROUND: The serotonin hypothesis of depression proposes that diminished serotonergic (5-HT) neurotransmission is causal in the pathophysiology of the disorder. Although the hypothesis is over 50 years old, there is no firm in vivo evidence for diminished 5-HT neurotransmission. We recently demonstrated that the 5-HT2A receptor agonist positron emission tomography (PET) radioligand [11C]Cimbi-36 is sensitive to increases in extracellular 5-HT induced by an acute d-amphetamine challenge. Here we applied [11C]Cimbi-36 PET to compare brain 5-HT release capacity in patients experiencing a major depressive episode (MDE) to that of healthy control subjects (HCs) without depression. METHODS: Seventeen antidepressant-free patients with MDE (3 female/14 male, mean age 44 ± 13 years, Hamilton Depression Rating Scale score 21 ± 4 [range 16-30]) and 20 HCs (3 female/17 male, mean age 32 ± 9 years) underwent 90-minute dynamic [11C]Cimbi-36 PET before and 3 hours after a 0.5-mg/kg oral dose of d-amphetamine. Frontal cortex (main region of interest) 5-HT2A receptor nondisplaceable binding was calculated from kinetic analysis using the multilinear analysis-1 approach with the cerebellum as the reference region. RESULTS: Following d-amphetamine administration, frontal nondisplaceable binding potential (BPND) was significantly reduced in the HC group (1.04 ± 0.31 vs. 0.87 ± 0.24, p < .001) but not in the MDE group (0.97 ± 0.25 vs. 0.92 ± 0.22, not significant). ΔBPND of the MDE group was significantly lower than that of the HC group (HC: 15% ± 14% vs. MDE: 6.5% ± 20%, p = .041). CONCLUSIONS: This first direct assessment of 5-HT release capacity in people with depression provides clear evidence for dysfunctional serotonergic neurotransmission in depression by demonstrating reduced 5-HT release capacity in patients experiencing an MDE.
Onwordi EC, Whitehurst T, Shatalina E, et al., 2023, Synaptic terminal density early in the course of schizophrenia: an in vivo UCB-J positron emission tomographic imaging study of synaptic vesicle glycoprotein 2A (SV2a)., Biological Psychiatry, ISSN: 0006-3223
BACKGROUND: The synaptic hypothesis is an influential theory of the pathoaetiology of schizophrenia. Supporting this, there is lower uptake of the synaptic terminal density marker UCB-J in patients with chronic schizophrenia compared to controls. However, it is unclear whether these differences are present early in the illness. To address this, we investigated [11C]UCB-J volume of distribution (VT) in antipsychotic-naïve/free patients with schizophrenia (SCZ) recruited from first-episode services compared to healthy volunteers (HV). METHODS: Forty-two volunteers (SCZ n = 21, HV n = 21) underwent [11C]UCB-J positron emission tomography to index [11C]UCB-J VT and distribution volume ratio (DVR) in the anterior cingulate, frontal, and dorsolateral prefrontal cortices, temporal, parietal and occipital lobes, hippocampus, thalamus and amygdala. Symptom severity was assessed in the SCZ group using the Positive and Negative Syndrome Scale (PANSS). RESULTS: We found no significant effects of group on [11C]UCB-J VT or DVR in most regions of interest (effect sizes from d=0.0 to 0.7, p>0.05), other than lower DVR in the temporal lobe (d=0.7, uncorrected p<0.05) and lower VT/fp in the anterior cingulate cortex in patients (d=0.7, uncorrected p<0.05). PANSS total score was negatively associated with [11C]UCB-J VT in the hippocampus in the SCZ group (r =-0.48, p=0.03). CONCLUSIONS: These findings indicate that large differences in synaptic terminal density are not present early in schizophrenia, although there may be more subtle effects. When taken with prior evidence of lower [11C]UCB-J VT in patients with chronic illness, this may indicate synaptic density changes during the course of schizophrenia.
Dadu A, Satone VK, Kaur R, et al., 2023, Application of Aligned-UMAP to longitudinal biomedical studies, Patterns, Vol: 4
High-dimensional data analysis starts with projecting the data to low dimensions to visualize and understand the underlying data structure. Several methods have been developed for dimensionality reduction, but they are limited to cross-sectional datasets. The recently proposed Aligned-UMAP, an extension of the uniform manifold approximation and projection (UMAP) algorithm, can visualize high-dimensional longitudinal datasets. We demonstrated its utility for researchers to identify exciting patterns and trajectories within enormous datasets in biological sciences. We found that the algorithm parameters also play a crucial role and must be tuned carefully to utilize the algorithm's potential fully. We also discussed key points to remember and directions for future extensions of Aligned-UMAP. Further, we made our code open source to enhance the reproducibility and applicability of our work. We believe our benchmarking study becomes more important as more and more high-dimensional longitudinal data in biomedical research become available.
Roussakis A, Gennaro M, Gordon MF, et al., 2023, A PET-CT study on neuroinflammation in Huntington’s patients participating in a randomised trial with laquinimod, Brain Communications, Vol: 5, Pages: 1-10, ISSN: 2632-1297
Microglia activation, an indicator of central nervous system inflammation, is believed to contribute to the pathology of Huntington’s disease. Laquinimod is capable of regulating microglia. By targeting the translocator protein, 11C-PBR28 PET-CT imaging can be used to assess the state of regional gliosis in vivo and explore the effects of laquinimod treatment. This study relates to the LEGATO-HD, multi-centre, double-blinded, Phase 2 clinical trial with laquinimod (US National Registration: NCT02215616). Fifteen patients of the UK LEGATO-HD cohort (mean age: 45.2 ± 7.4 years; disease duration: 5.6 ± 3.0 years) were treated with laquinimod (0.5 mg, N = 4; 1.0 mg, N = 6) or placebo (N = 5) daily. All participants had one 11C-PBR28 PET-CT and one brain MRI scan before laquinimod (or placebo) and at the end of treatment (12 months apart). PET imaging data were quantified to produce 11C-PBR28 distribution volume ratios. These ratios were calculated for the caudate and putamen using the reference Logan plot with the corpus callosum as the reference region. Partial volume effect corrections (Müller–Gartner algorithm) were applied. Differences were sought in Unified Huntington’s Disease Rating Scale scores and regional distribution volume ratios between baseline and follow-up and between the two treatment groups (laquinimod versus placebo). No significant change in 11C-PBR28 distribution volume ratios was found post treatment in the caudate and putamen for both those treated with laquinimod (N = 10) and those treated with placebo (N = 5). Over time, the patients treated with laquinimod did not show a significant clinical improvement. Data from the 11C-PBR28 PET-CT study indicate that laquinimod may not have affected regional translocator protein expression and clinical performance over the studied period.
Seibyl JP, DuBois JM, Racine A, et al., 2023, A Visual Interpretation Algorithm for Assessing Brain Tauopathy with 18F-MK-6240 PET., J Nucl Med, Vol: 64, Pages: 444-451
In vivo characterization of pathologic deposition of tau protein in the human brain by PET imaging is a promising tool in drug development trials of Alzheimer disease (AD). 6-(fluoro-18F)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine (18F-MK-6240) is a radiotracer with high selectivity and subnanomolar affinity for neurofibrillary tangles that shows favorable nonspecific brain penetration and excellent kinetic properties. The purpose of the present investigation was to develop a visual assessment method that provides both an overall assessment of brain tauopathy and regional characterization of abnormal tau deposition. Methods: 18F-MK-6240 scans from 102 participants (including cognitively normal volunteers and patients with AD or other neurodegenerative disorders) were reviewed by an expert nuclear medicine physician masked to each participant's diagnosis to identify common patterns of brain uptake. This initial visual read method was field-tested in a separate, nonoverlapping cohort of 102 participants, with 2 additional naïve readers trained on the method. Visual read outcomes were compared with semiquantitative assessments using volume-of-interest SUV ratio. Results: For the visual read, the readers assessed 8 gray-matter regions per hemisphere as negative (no abnormal uptake) or positive (1%-25% of the region involved, 25%-75% involvement, or >75% involvement) and then characterized the tau binding pattern as positive or negative for evidence of tau and, if positive, whether brain uptake was in an AD pattern. The readers demonstrated agreement 94% of the time for overall positivity or negativity. Concordance on the determination of regional binary outcomes (negative or positive) showed agreement of 74.3% and a Fleiss κ of 0.912. Using clinical diagnosis as the ground truth, the readers demonstrated a sensitivity of 73%-79% and specificity of 91%-93%, with a combined reader-concordance sensitivity of 80% and specificity of 93%. The average S
Jovalekic A, Roé-Vellvé N, Koglin N, et al., 2023, Validation of quantitative assessment of florbetaben PET scans as an adjunct to the visual assessment across 15 software methods, European Journal of Nuclear Medicine and Molecular Imaging, ISSN: 1619-7070
Purpose: Amyloid positron emission tomography (PET) with [18F]florbetaben (FBB) is an established tool for detecting Aβ deposition in the brain in vivo based on visual assessment of PET scans. Quantitative measures are commonly used in the research context and allow continuous measurement of amyloid burden. The aim of this study was to demonstrate the robustness of FBB PET quantification. Methods: This is a retrospective analysis of FBB PET images from 589 subjects. PET scans were quantified with 15 analytical methods using nine software packages (MIMneuro, Hermes BRASS, Neurocloud, Neurology Toolkit, statistical parametric mapping (SPM8), PMOD Neuro, CapAIBL, non-negative matrix factorization (NMF), AmyloidIQ) that used several metrics to estimate Aβ load (SUVR, centiloid, amyloid load, and amyloid index). Six analytical methods reported centiloid (MIMneuro, standard centiloid, Neurology Toolkit, SPM8 (PET only), CapAIBL, NMF). All results were quality controlled. Results: The mean sensitivity, specificity, and accuracy were 96.1 ± 1.6%, 96.9 ± 1.0%, and 96.4 ± 1.1%, respectively, for all quantitative methods tested when compared to histopathology, where available. The mean percentage of agreement between binary quantitative assessment across all 15 methods and visual majority assessment was 92.4 ± 1.5%. Assessments of reliability, correlation analyses, and comparisons across software packages showed excellent performance and consistent results between analytical methods. Conclusion: This study demonstrated that quantitative methods using both CE marked software and other widely available processing tools provided comparable results to visual assessments of FBB PET scans. Software quantification methods, such as centiloid analysis, can complement visual assessment of FBB PET images and could be used in the future for identification of early amyloid deposition, monitoring disease progression and treatment effectiveness.
Bohorquez SS, Constantinescu C, Manser PT, et al., 2022, In Vivo Head-To-Head Comparison of [<sup>18</sup>F]GTP1 and [<sup>18</sup>F]PI2620 in Alzheimer’s Disease, Alzheimer's and Dementia, Vol: 18, ISSN: 1552-5260
Background: Several radiotracers targeting tau pathology in Alzheimer’s disease (AD) are being used in human studies. Although abundant imaging characterization data exist for individual tracers there are only sparse in vivo data directly comparing tracers in head-to-head studies. As the use of tau PET increases, it is of paramount importance to enable multi-tracer, multi-center, multi-national observational and therapeutic trials. We present the direct in vivo comparison of [18F]GTP1 and [18F]PI2620. Methods: To date, 21 subjects (70±6 years; 12F) have completed imaging with both [18F]GTP1 and [18F]PI2620: 10 prodromal, 9 mild, one moderate AD subjects (Aβ+), and one Aβ- cognitively unimpaired subject. Thirty minutes images were acquired 60 and 45 min after [18F]GTP1 and [18F]PI2620 administration, respectively. SUVR was calculated using the inferior cerebellum and used to compare tau-specific binding and off-target signal characteristics between the two tracers. The choroid plexus was defined manually for each subject. The whole cortical gray (WCG) and cerebellum rims were defined using the gray and white-matter SPM tissue segmentation images (Figure 1). Results: Tracer distribution was similar for both tracers (Figures 2 and 3). Hammer atlas cortical SUVRs were linearly correlated (r2=0.88). Higher cortical [18F]PI2620 SUVR were observed in some subjects and regions (Figure 3). A lower SUVR correlation was observed in subcortical regions (r2=0.57). Regional comparisons are shown in Figure 4. Conclusions: The tau pathology distribution was similar for both tracers although each tracer presents a distinct off-target signal pattern. These preliminary results support the development of categorical and standardized quantification scales for using both tracers in future studies and bridging existing data sets. Figure 1. Delineation of cortex and cerebellum rims. The combined gray and white matter SPM segmentations were binarized and the ventricle
Tempest P, Lin YS, Tai CY, et al., 2022, PROGRESS IN DEVELOPING A LIGHT-STABLE 4R TAU PET IMAGING AGENT: APN-1701 FIH, Alzheimer's and Dementia, Vol: 18, ISSN: 1552-5260
Background: The need for a light stable 4R tau PET tracer for use in diverse tauopathies is widely appreciated. We aimed to assess the initial human imaging profile of [18F]APN-1701 as such a tracer and to compare its imaging profile to the well-established but light-sensitive tracer [18F]-APN-1607 that can detect 4R aggregates as well as 3R and mixed 3R/4R aggregates. [18F]APN-1607 has progressed to a multicenter Phase 2 clinical trial for Alzheimer’s disease (AD); therefore, prior imaging data with it was considered valuable for comparison. Method: One cognitively normal (CN) subject (male, 73yo) and one AD subject (female, 58 yo), who had undergone prior amyloid profiling using [18F]florbetapir PET and subsequent imaging with [18F]APN-1607 in a proof-of-concept study and a test-retest study, respectively, participated in the current study. Dynamic imaging with [18F]APN-1701 was performed over 180 min to obtain kinetic data. Result: Overall, for both subjects [18F]APN-1701 generally matched [18F]APN-1607 findings, i.e., peak SUV values reached similar levels. The CN subject, who was amyloid negative, had slight, uniform cortical [18F]-APN-1701 uptake and more substantial uptake in the pallidum, pons and midbrain. SUVr images for the AD subject showed retention in similar brain regions for both tau tracers with the same rank order of regional SUV/SUVr. Notably, for this subject [18F]APN-1701 continued to accumulate up to the end of image acquisition. Conclusion: [18F]APN-1701 demonstrates cortical uptake generally similar to [18F]APN-1607 but its slow kinetics are unfavorable for further development.
Ng B, Rowland HA, Wei T, et al., 2022, Neurons derived from individual early Alzheimer's disease patients reflect their clinical vulnerability, BRAIN COMMUNICATIONS, Vol: 4
Halff EF, Natesan S, Bonsall DR, et al., 2022, Evaluation of Intraperitoneal [F-18]-FDOPA Administration for Micro-PET Imaging in Mice and Assessment of the Effect of Subchronic Ketamine Dosing on Dopamine Synthesis Capacity, MOLECULAR IMAGING, Vol: 2022
Mohamed MA, Zeng Z, Gennaro M, et al., 2022, Astrogliosis in aging and Parkinson’s disease dementia: a new clinical study with 11C-BU99008 PET, Brain Communications, Vol: 4, ISSN: 2632-1297
The role of astrogliosis in the pathology of brain aging and neurodegenerative diseases has recently drawn great attention. Imidazoline-2 binding sites (I2BS) represent a possible target to map the distribution of reactive astrocytes. In this study, we use 11C-BU99008, an I2BS-specific PET radioligand, to image reactive astrocytes in vivo in healthy controls (HCs) andpatients with established Parkinson’s disease dementia (PDD).Eighteen HCs (age: 45−78 years) and six patients with PDD (age: 64−77 years) had one 11C-BU99008 PET-CT scan with arterial input function. All subjects underwent one 3T MRI brain scan to facilitate the analysis of the PET-CT data and to capture individual cerebral atrophy. Regional 11C-BU99008 volumes of distribution (VT) were calculated for each subject by two-tissue compartmental modelling.Positive correlations between 11C-BU99008 VT values and age were found for all tested regions across the brain within HCs (p<0.05); furthermore, multiple regression indicated that aging affects 11C-BU99008 VT values in a region-specific manner. Independent samples t-test indicated that there was no significant group difference in 11C-BU99008 VT values betweenPDD (n=6; mean age = 71.97±4.66 years) and older HCs (n=9; mean age = 71.90±5.51 years).Our dataset shows that astrogliosis is common with aging in a region-specific manner. However, in this set-up, 11C-BU99008 PET cannot differentiate patients with PDD from healthy controls of similar age.
Venkataraman A, Mansur A, Rizzo G, et al., 2022, Widespread cell stress and mitochondrial dysfunction occur in patients with early Alzheimer’s Disease, Science Translational Medicine, Vol: 14, Pages: 1-11, ISSN: 1946-6234
Cell stress and impaired oxidative phosphorylation are central to mechanisms of synaptic loss and neurodegeneration in the cellular pathology of Alzheimer’s disease (AD). In this study, we quantified the in vivo expression of the endoplasmic reticulum stress marker, sigma 1 receptor (S1R), using [11C]SA4503 PET, the mitochondrial complex I (MC1) with [18F]BCPP-EF and the pre-synaptic vesicular protein SV2A with [11C]UCB-J in 12 patients with early AD and in 16 cognitively normal controls. We integrated these molecular measures with assessments of regional brain volumes and cerebral blood flow (CBF) measured with magnetic resonance imaging (MRI) arterial spin labelling. Eight patients with AD were followed longitudinally to estimate the rate of change of the physiological and structural pathology markers with disease progression. The patients showed widespread increases in S1R (≤ 27%) and regional reduction in MC1 (≥ -28%) and SV2A (≥ -25%) radioligand binding, brain volume (≥ -23%), and CBF (≥ -26%). [18F]BCPP-EF PET MC1 binding (≥ -12%) and brain volumes (≥ -5%) showed progressive reductions over 12-18 months, suggesting that they both could be used as pharmacodynamic indicators in early-stage therapeutics trials. Associations of reduced MC1 and SV2A and increased S1R radioligand binding with reduced cognitive performance in AD, although exploratory, suggested a loss of metabolic functional reserve with disease. Our study thus provides in vivo evidence for widespread, clinically relevant cellular stress and bioenergetic abnormalities in early AD.
Livingston NR, Calsolaro V, Hinz R, et al., 2022, Relationship between astrocyte reactivity, using novel C-11-BU99008 PET, and glucose metabolism, grey matter volume and amyloid load in cognitively impaired individuals, MOLECULAR PSYCHIATRY, Vol: 27, Pages: 2019-2029, ISSN: 1359-4184
Syvänen S, Gunn RN, Zhang L, 2022, Principles of PET and Its Role in Understanding Drug Delivery to the Brain, AAPS Advances in the Pharmaceutical Sciences Series, Pages: 329-352
Positron emission tomography (PET) is a noninvasive medical imaging technique that enables the investigation of drug pharmacokinetics in vivo. The technique is especially powerful for pharmacokinetic studies of new CNS drug candidates as tissue samples from the brain are understandably difficult to obtain. The PET technique involves the administration of a radiolabeled molecule, often referred to as a PET radiotracer, whose spatiotemporal distribution can be measured using tomography. The radiolabeled molecule can be the drug under investigation, a structurally different molecule that binds to the same target as the drug candidate, or a molecule that interacts with a downstream target that is believed to be affected by the action of the drug candidate. Such radiolabeled probes allow PET to address several questions central for CNS drug development: Does the drug candidate reach the target site? Does the drug candidate interact with the desired target? Is the concentration of the drug at the target site sufficient to illicit an effect? What is the temporal nature of such an interaction? What is the relationship between the target site concentration and the administered dose and/or plasma concentrations?.
Reynolds S, Kazan SM, Anton A, et al., 2021, Kinetic modelling of dissolution dynamic nuclear polarisation C-13 magnetic resonance spectroscopy data for analysis of pyruvate delivery and fate in tumours, NMR IN BIOMEDICINE, Vol: 35, ISSN: 0952-3480
Venkataraman A, Bishop C, Mansur A, et al., 2021, Imaging synaptic microstructure and synaptic loss in vivo in early Alzheimer’s Disease, Publisher: Cold Spring Harbor Laboratory
Background Synaptic loss and neurite dystrophy are early events in Alzheimer’s Disease (AD). We aimed to characterise early synaptic microstructural changes in vivo.Methods MRI neurite orientation dispersion and density imaging (NODDI) and diffusion tensor imaging (DTI) were used to image cortical microstructure in both sporadic, late onset, amyloid PET positive AD patients and healthy controls (total n = 28). We derived NODDI measures of grey matter extracellular free water (FISO), neurite density (NDI) and orientation dispersion (ODI), which provides an index of neurite branching and orientation, as well as more conventional DTI measures of fractional anisotropy (FA), mean/axial/radial diffusivity (MD, AD, RD, respectively). We also performed [11C]UCB-J PET, which provides a specific measure of the density of pre-synaptic vesicular protein SV2A. Both sets of measures were compared to regional brain volumes.Results The AD patients showed expected relative decreases in regional brain volumes (range, -6 to - 23%) and regional [11C]UCB-J densities (range, -2 to -25%). Differences between AD and controls were greatest in the hippocampus. NODDI microstructural measures showed greater FISO (range, +26 to +44%) in AD, with little difference in NDI (range, -1 to +7%) and mild focal changes in ODI (range, -4 to +3%). Regionally greater FISO and lower [11C]UCB-J binding were correlated across grey matter in patients (most strongly in the caudate, r2 = 0.37, p = 0.001). FISO and DTI RD were strongly positively associated, particularly in the hippocampus (r2 = 0.98, p < 7.4 × 10−9). After 12-18 months we found a 5% increase in FISO in the temporal lobe, but little change across all ROIs in NDI and ODI. An exploratory analysis showed higher parietal lobe FISO was associated with lower language scores in people with AD.Conclusions We interpreted the increased extracellular free water as a possible consequence of glial activation. The dynamic range of disease
Mansur A, Rizzo G, Rabiner EA, et al., 2021, Simultaneous multi-parameter multi-tracer estimation with dynamic neuro-PET data, Publisher: SAGE PUBLICATIONS INC, Pages: 216-217, ISSN: 0271-678X
Rizzo G, Searle GE, Passchier J, et al., 2021, Determination of the 5-HT2C receptor fraction in the human hippocampus in vivo: A [C-11]Cimbi-36 PET study, Publisher: SAGE PUBLICATIONS INC, Pages: 234-236, ISSN: 0271-678X
Rabiner EA, Uz T, Mansur A, et al., 2021, Endogenous dopamine release in the human brain as a pharmacodynamic biomarker: evaluation of the new GPR139 agonist TAK-041 with [C-11]PHNO PET, NEUROPSYCHOPHARMACOLOGY, Vol: 47, Pages: 1405-1412, ISSN: 0893-133X
Veronese M, Rizzo G, Belzunce M, et al., 2021, Reproducibility of findings in modern PET neuroimaging: insight from the NRM2018 grand challenge, Journal of Cerebral Blood Flow and Metabolism, Vol: 41, Pages: 2778-2796, ISSN: 0271-678X
The reproducibility of findings is a compelling methodological problem that the neuroimaging community is facing these days. The lack of standardized pipelines for image processing, quantification and statistics plays a major role in the variability and interpretation of results, even when the same data are analysed. This problem is well-known in MRI studies, where the indisputable value of the method has been complicated by a number of studies that produce discrepant results. However, any research domain with complex data and flexible analytical procedures can experience a similar lack of reproducibility. In this paper we investigate this issue for brain PET imaging. During the 2018 NeuroReceptor Mapping conference, the brain PET community was challenged with a computational contest involving a simulated neurotransmitter release experiment. Fourteen international teams analysed the same imaging dataset, for which the ground-truth was known. Despite a plurality of methods, the solutions were consistent across participants, although not identical. These results should create awareness that the increased sharing of PET data alone will only be one component of enhancing confidence in neuroimaging results and that it will be important to complement this with full details of the analysis pipelines and procedures that have been used to quantify data.
Whittington A, Gunn RN, Alzheimers Disease Neuroimaging Initiative, 2021, TauIQ: a canonical image based algorithm to quantify tau PET scans., Journal of Nuclear Medicine, Vol: 62, Pages: 1292-1300, ISSN: 0161-5505
Recently, AmyloidIQ was introduced as a new canonical image-based algorithm to quantify amyloid PET scans and demonstrated increased power over traditional SUV ratio (SUVR) approaches when assessed in cross-sectional and longitudinal analyses. We build further on this mathematical framework to develop a TauIQ algorithm for the quantitative analysis of the more complex spatial distribution displayed by tau PET radiotracers. Methods: Cross-sectional (n = 615) and longitudinal (n = 149) 18F-flortaucipir data were obtained from the Alzheimer's Disease Neuroimaging Initiative along with necessary adjunct amyloid PET and T1-weighted structural MRI data. A subset of these data were used to derive a chronological tau dataset, using AmyloidIQ analysis of associated amyloid PET data to calculate the subject's temporal position in the canonical AD disease process, from which canonical images for the nonspecific and specific binding components of 18F-flortaucipir in AD were calculated. These 2 canonical images were incorporated into the TauIQ algorithm that enables the quantification of both global and local tau outcome measures using an image-based regression and statistical parametric analysis of the initial residual image. Performance of the TauIQ algorithm was compared with SUVR approaches for cross-sectional analyses, longitudinal analyses, and correlation with clinical measures (Alzheimer Disease Assessment Scale-Cognitive Subscale [ADAS-Cog], Clinical Dementia Rating scale-sum of boxes [CDR-SB], and Mini-Mental State Examination [MMSE]). Results: TauIQ successfully calculated global tau load (TauL) in all 791 scans analyzed (range, -3.5% to 185.2%; mean ± SD, 23% ± 20.5%) with a nonzero additional local tau component being required in 31% of all scans (cognitively normal [CN], 22%; mild cognitive impairment [MCI], 35%; dementia, 72%). TauIQ was compared with the best SUVR approach in the cross-sectional analysis (TauL increase in effect size: CN- vs. CN+, +
Venkataraman A, Mansur A, Rizzo G, et al., 2021, Widespread cell stress and mitochondrial dysfunction in early Alzheimer’s Disease, Publisher: MedRxiv
Cell stress and impaired oxidative phosphorylation are central to mechanisms of synaptic loss and neurodegeneration in the cellular pathology of Alzheimer’s disease (AD). We quantified the in vivo density of the endoplasmic reticulum stress marker, the sigma 1 receptor (S1R) using [11C]SA4503 PET, as well as that of mitochondrial complex I (MC1) with [18F]BCPP-EF and the pre-synaptic vesicular protein SV2A with [11C]UCB-J in 12 patients with early AD and in 16 cognitively normal controls. We integrated these molecular measures with assessments of regional brain volumes and brain perfusion (CBF) measured with MRI arterial spin labelling. 8 AD patients were followed longitudinally to estimate rates of change with disease progression over 12-18 months. The AD patients showed widespread increases in S1R (≤ 27%) and regional decreases in MC1 (≥ -28%), SV2A (≥ -25%), brain volume (≥ -23%), and CBF (≥ -26%). [18F]BCPP-EF PET MC1 density (≥ -12%) and brain volumes (≥ -5%) were further reduced at follow up in brain regions consistent with the differences between AD patients and controls at baseline. Exploratory analyses showing associations of MC1, SV2A and S1R density with cognitive changes at baseline and longitudinally with AD, but not in controls, suggested a loss of metabolic functional reserve with disease. Our study thus provides novel in vivo evidence for widespread cellular stress and bioenergetic abnormalities in early AD and that they may be clinically meaningful.
Onwordi EC, Whitehurst T, Mansur A, et al., 2021, The relationship between synaptic density marker SV2A, glutamate and N-acetyl aspartate levels in healthy volunteers and schizophrenia: a multimodal PET and magnetic resonance spectroscopy brain imaging study, Translational Psychiatry, Vol: 11, Pages: 1-9, ISSN: 2158-3188
Glutamatergic excitotoxicity is hypothesised to underlie synaptic loss in schizophrenia pathogenesis, but it is unknown whether synaptic markers are related to glutamatergic function in vivo. Additionally, it has been proposed that N-acetyl aspartate (NAA) levels reflect neuronal integrity. Here, we investigated whether synaptic vesicle glycoprotein 2 A (SV2A) levels are related to glutamatergic markers and NAA in healthy volunteers (HV) and schizophrenia patients (SCZ). Forty volunteers (SCZ n = 18, HV n = 22) underwent [11C]UCB-J positron emission tomography and proton magnetic resonance spectroscopy (1H-MRS) imaging in the left hippocampus and anterior cingulate cortex (ACC) to index [11C]UCB-J distribution volume ratio (DVR), and creatine-scaled glutamate (Glu/Cr), glutamate and glutamine (Glx/Cr) and NAA (NAA/Cr). In healthy volunteers, but not patients, [11C]UCB-J DVR was significantly positively correlated with Glu/Cr, in both the hippocampus and ACC. Furthermore, in healthy volunteers, but not patients, [11C]UCB-J DVR was significantly positively correlated with Glx/Cr, in both the hippocampus and ACC. There were no significant relationships between [11C]UCB-J DVR and NAA/Cr in the hippocampus or ACC in healthy volunteers or patients. Therefore, an appreciable proportion of the brain 1H-MRS glutamatergic signal is related to synaptic density in healthy volunteers. This relationship is not seen in schizophrenia, which, taken with lower synaptic marker levels, is consistent with lower levels of glutamatergic terminals and/or a lower proportion of glutamatergic relative to GABAergic terminals in the ACC in schizophrenia.
Calsolaro V, Matthews PM, Donat CK, et al., 2021, Astrocyte reactivity with late onset cognitive impairment assessed in-vivo using 11C-BU99008 PET and its relationship with amyloid load, Molecular Psychiatry, Vol: 26, Pages: 5848-5855, ISSN: 1359-4184
11C-BU99008 is a novel positron emission tomography (PET) tracer that enables selective imaging of astrocyte reactivity in vivo. To explore astrocyte reactivity associated with Alzheimer’s disease, 11 older, cognitively impaired (CI) subjects and 9 age-matched healthy controls (HC) underwent 3T magnetic resonance imaging (MRI), 18F-florbetaben and 11C-BU99008 PET. The 8 amyloid (Aβ)-positive CI subjects had higher 11C-BU99008 uptake relative to HC across the whole brain, but particularly in frontal, temporal, medial temporal and occipital lobes. Biological parametric mapping demonstrated a positive voxel-wise neuroanatomical correlation between 11C-BU99008 and 18F-florbetaben. Autoradiography using 3H-BU99008 with post-mortem Alzheimer’s brains confirmed through visual assessment that increased 3H-BU99008 binding localised with the astrocyte protein glial fibrillary acid protein and was not displaced by PiB or florbetaben. This proof-of-concept study provides direct evidence that 11C-BU99008 can measure in vivo astrocyte reactivity in people with late-life cognitive impairment and Alzheimer’s disease. Our results confirm that increased astrocyte reactivity is found particularly in cortical regions with high Aβ load. Future studies now can explore how clinical expression of disease varies with astrocyte reactivity.
Marques TR, Natesan S, Rabiner EA, et al., 2021, Adenosine A(2A) receptor in schizophrenia: an in vivo brain PET imaging study, PSYCHOPHARMACOLOGY, Vol: 239, Pages: 3439-3445, ISSN: 0033-3158
Bucci M, Savitcheva I, Farrar G, et al., 2021, A multisite analysis of the concordance between visual image interpretation and quantitative analysis of [F-18]flutemetamol amyloid PET images, EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING, Vol: 48, Pages: 2183-2199, ISSN: 1619-7070
Mansur A, Rabiner EA, Tsukada H, et al., 2021, Test-retest variability and reference region-based quantification of 18F-BCPP-EF for imaging mitochondrial complex I in the human brain, Journal of Cerebral Blood Flow and Metabolism, Vol: 41, Pages: 771-779, ISSN: 0271-678X
Mitochondrial complex I (MC-I) is an essential regulator of brain bioenergetics and can be quantified in the brain using PET radioligand 18F-BCPP-EF. Here we evaluate the test-retest reproducibility of 18F-BCPP-EF in humans, and assess the use of a non-invasive quantification method (standardised uptake value ratio - SUVR). Thirty healthy volunteers had a 90-min dynamic 18F-BCPP-EF scan with arterial blood sampling, five of which received a second scan to be included in the test-retest analysis. Time-activity curves (TAC) were analysed using multilinear analysis 1 (MA1) and the two-tissue compartment model (2TC) to estimate volumes of distribution (VT). Regional SUVR-1 values were calculated from the 70 to 90-min TAC data using the centrum semiovale as a pseudo reference region, and compared to kinetic analysis-derived outcome measures. The mean absolute test-retest variability of VT ranged from 12% to 18% across regions. Both DVR-1and SUVR-1 had improved test-retest variability in the range 2%-7%. SUVR-1 was highly correlated with DVR-1 (r2 = 0.97, n = 30). In conclusion, 18F-BCPP-EF has suitable test-retest reproducibility and can be used to quantify MC-I in clinical studies.
Wadhwa P, Thielemans K, Efthimiou N, et al., 2021, PET image reconstruction using physical and mathematical modelling for time of flight PET-MR scanners in the STIR library, METHODS, Vol: 185, Pages: 110-119, ISSN: 1046-2023
Ashok AH, Myers J, Frost G, et al., 2021, Acute acetate administration increases endogenous opioid levels in the human brain: A [C-11]carfentanil molecular imaging study, JOURNAL OF PSYCHOPHARMACOLOGY, Vol: 35, Pages: 606-610, ISSN: 0269-8811
Chen DL, Ballout S, Chen L, et al., 2020, Consensus Recommendations on the Use of F-18-FDG PET/CT in Lung Disease, JOURNAL OF NUCLEAR MEDICINE, Vol: 61, ISSN: 0161-5505
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