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Objective To determine whether state-associated changes in microglial activity, measured with translocator-protein positron emission tomography (TSPO PET), can be identified in psychosis patients through longitudinal evaluation of their regional tracer uptake over the clinical course from acute psychosis to post-treatment follow-up, and comparison to healthy controls. We also evaluated the relation between tracer uptake, clinical symptoms and peripheral immunological markers. Method Second-generation radioligand [18F]-PBR111 TSPO PET-CT was used for longitudinal dynamic imaging in 14 male psychosis patients and 17 male age-matched healthy control subjects. Patients were first scanned during an acute psychotic episode followed by a second scan after treatment. Prior genotyping of subjects for the rs6917 polymorphism distinguished high- and mixed-affinity binders. The main outcome was regional volume of distribution (VT), representing TSPO binding. Plasma concentrations of CRP, cytokines and kynurenines were measured at each timepoint. Results We found a significant three-way interaction between time of scan, age and cohort (cortical grey matter F6.50, p.020). Age-dependent differences in VT existed between cohorts during the psychotic state, but not at follow-up. Patients’ relative change in VT over time correlated with age (cortical grey matter Pearson’s r.574). PANSS positive subscale scores correlated with regional VT during psychosis (cortical grey matter r.767). Plasma CRP and quinolinic acid were independently associated with lower VT. Conclusions We identified a differential age-dependent pattern of TSPO binding from psychosis to follow-up in our cohort of male psychosis patients. We recommend future TSPO PET studies in psychosis patients to differentiate between clinical states and consider potential age-related effects.

Disease-modifying treatment trials are increasingly advanced to the prodromal or preclinical phase of Alzheimer's disease (AD), and inclusion criteria are based on biomarkers rather than clinical symptoms. Therefore, it is of great interest to determine which biomarkers should be combined to accurately predict conversion from mild cognitive impairment (MCI) to AD dementia. However, up to date, only few studies performed a complete A/T/N subject characterization using each of the CSF and imaging markers, or they only investigated long-term (≥ 2 years) prognosis. This study aimed to investigate the association between cerebrospinal fluid (CSF), magnetic resonance imaging (MRI), amyloid- and 18F-FDG positron emission tomography (PET) measures at baseline, in relation to cognitive changes and conversion to AD dementia over a short-term (12-month) period. We included 13 healthy controls, 49 MCI and 16 AD dementia patients with a clinical-based diagnosis and a complete A/T/N characterization at baseline. Global cortical amyloid-β (Aβ) burden was quantified using the 18F-AV45 standardized uptake value ratio (SUVR) with two different reference regions (cerebellar grey and subcortical white matter), whereas metabolism was assessed based on 18F-FDG SUVR. CSF measures included Aβ1–42, Aβ1–40, T-tau, P-tau181, and their ratios, and MRI markers included hippocampal volumes (HV), white matter hyperintensities, and cortical grey matter volumes. Cognitive functioning was measured by MMSE and RBANS index scores. All statistical analyses were corrected for age, sex, education, and APOE ε4 genotype. As a result, faster cognitive decline was most strongly associated with hypometabolism (posterior cingulate) and smaller hippocampal volume (e.g., Δstory recall: β = +0.43 [p, Highlights • FDG-PET and MRI HV are the strongest predictors of cognitive decline and conversion to AD. • Combination of visuospatial construction testing with FDG-PET or MRI HV present high predicting power of conversion. • CSF and amyloid-PET seem less suitable markers of disease progression. • Increased AV45-PET predicts short-term cognitive decline if SUVR is referenced to WM instead of CB.

Introduction Dual-biomarker positron emission tomography (PET), providing complementary information on cerebral blood flow and amyloid-β deposition, is of clinical interest for Alzheimer's disease (AD). The purpose of this study was to validate the perfusion components of early-phase 18F-florbetapir (eAV45), the 18F-AV45 delivery rate (R1), and 18F-FDG against 15O-H2O PET and assess how they change with disease severity. Methods This study included ten controls, 19 amnestic mild cognitive impairment, and 10 AD dementia subjects. Within-subject regional correlations between modalities, between-group regional and voxel-wise analyses of covariance per modality, and receiver operating characteristic analyses for discrimination between groups were performed. Results FDG standardized uptake value ratio, eAV45 (0–2 min) standardized uptake value ratio, and AV45-R1 were significantly associated with H2O PET (regional Pearson r = 0.54–0.82, 0.70–0.94, and 0.65–0.92, respectively; P < .001). All modalities confirmed reduced cerebral blood flow in the posterior cingulate of patients with amnestic mild cognitive impairment and AD dementia, which was associated with lower cognition (r = 0.36–0.65, P < .025) and could discriminate between patient and control groups (area under the curve > 0.80). However, eAV45 was less sensitive to reflect the disease severity than AV45-R1 or FDG. Discussion R1 is preferable over eAV45 for accurate representation of brain perfusion in dual-biomarker PET for AD.

Increased brain uptake of [18F]-AV45 visualized by PET is a key biomarker for Alzheimers disease (AD). The standardized uptake value ratio (SUVR) is widely used for quantification, but is subject to variability based on choice of reference region and changes in cerebral blood flow. Here we validate the SUVR method against the gold standard volume of distribution (VT) to assess cross-sectional differences in plaque load. Methods: Dynamic 60-min [18F]-AV45 (291 ± 67 MBq) and 1-min [15O]-H2O (370 MBq) scans were obtained in 35 age-matched elderly subjects, including 10 probable AD dementia, 15 amnestic mild cognitive impairment (aMCI) and 10 cognitively healthy controls (HC). [18F]-AV45 VT was determined from two-tissue compartment modeling using a metabolite-corrected plasma input function. Static SUVR was calculated at 50-60 min p.i., using either cerebellar gray matter (SUVRCB) or whole subcortical white matter (SUVRWM) as reference. Additionally, whole cerebellum, pons, centrum semiovale and a composite region were examined as alternative references. Blood flow was quantified by [15O]-H2O SUV. Data are presented as mean ± standard error of the mean (SEM). Results: There was rapid metabolization of [18F]-AV45 with only 35% of unchanged parent remaining at 10 minutes. Compared to VT, differences in cortical Aβ-load between aMCI and AD were overestimated by SUVRWM (+4 ± 2%) and underestimated by SUVRCB (-10 ± 2%). VT correlated better with SUVRWM (Pearsons r: from 0.63 for posterior cingulate to 0.89 for precuneus, p < 0.0001) than with SUVRCB (Pearsons r: from 0.51 for temporal lobe (p = 0.002) to 0.82 for precuneus (p < 0.0001)) in all tested regions. Correlation results for the alternative references were in-between those for CB and WM. [15O]-H2O data showed that blood flow was decreased in AD compared to aMCI in cortical regions (-5 ± 1%) and in the reference regions (CB: -9 ± 8%, WM: -8 ± 8%). Conclusion: Increased brain uptake of [18F]-AV45 assessed by the simplified static SUVR protocol does not truly reflect Aβ load. However, SUVRWM is better correlated with VT and more closely reflects VT differences between aMCI and AD than SUVRCB.

Background: Evidence suggests that the concordance between amyloid-PET and cerebrospinal fluid (CSF) amyloid-beta (A beta) increases when the CSF A beta(1-42)/A beta(1-40) ratio is used as compared to CSF A beta(1-42) levels alone. Objective: In order to test this hypothesis, we set up a prospective longitudinal study comparing the concordance between different amyloid biomarkers for Alzheimer's disease (AD) in a clinical setting. Methods: Seventy-eight subjects (AD dementia (n = 17), mild cognitive impairment (MCI, n = 48), and cognitively healthy controls (n = 13)) underwent a [F-18] Florbetapir ([F-18]AV45) PET scan, [F-18] FDG PET scan, MRI scan, and an extensive neuropsychological examination. In a large subset (n = 67), a lumbar puncture was performed and AD biomarkers were analyzed (A beta(1-42), A beta(1-40), T-tau, P-tau(181)). Results: We detected an increased concordance in the visual and quantitative (standardized uptake value ratio (SUVR) and total volume of distribution (VT)) [F-18]AV45 PET measures when the CSF A beta(1-42)/A beta(1-40) was applied compared to A beta(1-42) alone. CSF biomarkers were stronger associated to [F-18]AV45 PET for SUVR values when considering the total brain white matter as reference region instead of cerebellar grey matter Conclusion: The concordance between CSF A beta and [F-18]AV45 PET increases when the CSF A beta(1-42)/A beta(1-40) ratio is applied. This finding is of most importance for the biomarker-based diagnosis of AD as well as for selection of subjects for clinical trials with potential disease-modifying therapies for AD.