AV-1451 Uptake Research Articles

In vivo braak staging using 18F-AV1451 Tau PET imaging

Alzheimer's disease (AD) related tau pathology has previously been classified into six consecutive Braak stages describing the gradual regional deposition of hyperphosphorylated tau protein over the course of the disease. Positron emission tomography (PET) using the ligand 18F-AV1451 (previously T807) now renders possible the in vivo assessment and staging of tau pathology and its relationship with cerebral glucose metabolism as measured with 18F-FDG. Nineteen elderly and two young normal controls (NCs), as well as eight AD patients (Table 1), underwent 18F-AV1451 PET scanning (80-100 min tissue ratio, cerebellar gray matter reference). Structural magnetic resonance (MR) images were co-registered to the respective PET images and segmented into regions of interest (ROIs) corresponding anatomically to the transentorhinal (I/II), limbic (III/IV), and isocortical (V/VI) Braak stages using FreeSurfer v5.1 (Figure 1). High AV1451 binding was identified by calculating a ratio of voxels > 2 SD above NC mean over total voxel count within each ROI. In addition, seventeen NCs and five AD patients also received 18F-FDG PET scans (30-60 min tissue ratio, pontine reference). Combined FreeSurfer ROIs We found clear separation of NCs from AD patients throughout all Braak stages (Figure 2). Linear regression identified higher AV1451 uptake in early stage Braak ROIs as being highly predictive of higher uptake in later stage Braak ROIs, independent of ApoE status or age (Figure 3). Furthermore, linear regression of mean 18F-AV1451 uptake in Braak ROIs on 18F-FDG uptake in a predefined set of ROIs covering regions typically susceptible for AD-related hypometabolism yielded significant negative relationships in Braak ROIs I/II and III/IV.

Comparison between PET template-based method and MRI-based method for cortical quantification of florbetapir (AV-45) uptake in vivo

PurposeFlorbetapir (AV-45) has been shown to be a reliable tool for assessing in vivo amyloid load in patients with Alzheimer’s disease from the early stages. However, nonspecific white matter binding has been reported in healthy subjects as well as in patients with Alzheimer’s disease. To avoid this issue, cortical quantification might increase the reliability of AV-45 PET analyses. In this study, we compared two quantification methods for AV-45 binding, a classical method relying on PET template registration (route 1), and a MRI-based method (route 2) for cortical quantification.MethodsWe recruited 22 patients at the prodromal stage of Alzheimer’s disease and 17 matched controls. AV-45 binding was assessed using both methods, and target-to-cerebellum mean global standard uptake values (SUVr) were obtained for each of them, together with SUVr in specific regions of interest. Quantification using the two routes was compared between the clinical groups (intragroup comparison), and between groups for each route (intergroup comparison). Discriminant analysis was performed.ResultsIn the intragroup comparison, differences in uptake values were observed between route 1 and route 2 in both groups. In the intergroup comparison, AV-45 uptake was higher in patients than controls in all regions of interest using both methods, but the effect size of this difference was larger using route 2. In the discriminant analysis, route 2 showed a higher specificity (94.1 % versus 70.6 %), despite a lower sensitivity (77.3 % versus 86.4 %), and D-prime values were higher for route 2.ConclusionThese findings suggest that, although both quantification methods enabled patients at early stages of Alzheimer’s disease to be well discriminated from controls, PET template-based quantification seems adequate for clinical use, while the MRI-based cortical quantification method led to greater intergroup differences and may be more suitable for use in current clinical research.Electronic supplementary materialThe online version of this article (doi:10.1007/s00259-013-2656-8) contains supplementary material, which is available to authorized users.

Association between memory and amyloid deposition and synaptic dysfunction in EMCI, LMCI and Alzheimer’s disease patients

Deficits in list of words or history recall performance is associated with regional declines in brain metabolism, neurodegeneration and amyloid deposition. However, little is known regarding the neurocorrelates of these tests in early stages of AD. Here we aimed to investigate the association between these tests and synaptic depletion and amyloid deposition measured by [18 F]FDG and [18 F]AV45 respectively We analyzed a subsample of participants from ADNIGO & ADNI2 who had clinical, neuropsychological, and [18F]AV45/[18F]FDG data collected in a single visit. Diagnosis of cognitively normal (CN), early mild cognitive impairment (EMCI), late mild cognitive impairment (LMCI) and AD was adjusted using ADNI2 guidelines. Scores on the Rey Auditory Verbal Learning Test 30 min delay (RAVLT30), total recall (RAVLTT), sum of trials (RAVLTST), Logical Memory 30 min delay (LM) were obtained from the ADNI database. RAVLTST was calculated by adding the 5 initial trials of the Rey Auditory Verbal Learning Test. T1 MRIs underwent non-uniformity correction, were skull-stripped and nonlinearly registered to MNI152 space. After registration to MRI, PET uptake ratios were calculated dividing [18F]AV45 and [18F]FDG scans by the median counts of cerebellar-gm and pons, respectively. PET images were subsequently registered to MNI152 space. Voxel-based (age corrected) regression between PET images and LM, RAVLT30, RAVLTT and RAVLST were calculated with PET-UR resampled to MNI space and blurred with a 6mm Gaussian filter. Demographics are summarized in table 1. [18 F]FDG uptake correlated positively (Figure 1) with RAVLT30 and RAVLTST in the hippocampus of EMCI. Hypometabolism correlated with LM (left hippocampus) in LMCI and with RAVLTST (temporal lobe) in AD. [18 F]AV45 uptake(Figure 2) correlated negatively with LM (temporal and parietal) and RAVLTT (parietal) in controls and with RAVLT30, RAVLTT and RAVLTST in the frontal and parietal lobes of EMCI. For all groups collapsed, all tests correlated with brain hypometabolism and [18 F]AV45 uptake in temporal, parietal and frontal areas RAVLT30 and RAVLTST convey neurodegeneration in EMCI while LM reflects neurodegeneration in LMCI. LM30 correlates with amyloid deposition only in controls, while RAVLT30, RAVLTT and RAVLTST reflect amyloidosis in EMCI. Shows significant correlation between [18F]FDG uptake ratio and Logical memory 30 min delay, Rey auditory verbal learning test 30 min delay (RAVLT30) and Rey auditory verbal learning test sum of trails (RAVLTST) scores in early and late MCI. Shows significant correlation between [18F]AV45 uptake ratio and Logical memory 30 min delay, Rey auditory verbal learning test 30 min delay Rey auditory verbal learning test total recall (RAVLTT) and Rey auditory verbal learning test sum of trials scores in controls and early MCI

Cortical florbetapir-PET amyloid load in prodromal Alzheimer’s disease patients

BackgroundFlorbetapir (AV-45) has been shown to be a reliable tool to assess amyloid load in patients with Alzheimer's disease (AD) at demential stages. Longitudinal studies also suggest that AV-45 has the ability to bind amyloid in the early stages of AD. In this study, we investigated AV-45 binding and its relation with cognitive performance in a group of patients at the prodromal stage of Alzheimer's disease, recruited according to strict inclusion criteria.MethodsWe recruited patients at the prodromal stage of AD and matched control subjects. AV-45 binding was assessed using an innovative extraction method allowing quantifying uptake in the cortex only. AV-45 uptake was compared between groups in the precuneus, posterior cingulate, anterior cingulate, and orbito-frontal regions. Correlations between AV-45 uptake and cognitive performance were assessed.ResultsTwenty-two patients and 17 matched control subjects were included in the study. We report a significant increase of cortical AV-45 uptake in the patients compared to the control subjects in all regions of interest. Specific correlations were found within the patient group between mean global amyloid cortical load and cognitive performance in three different memory tests.ConclusionsThese findings suggest that at the prodromal stage of AD, memory decline is linked to an increase of cortical β-amyloid load.

PET imaging with [18F]AV-45 in an APP/PS1-21 murine model of amyloid plaque deposition

Alzheimer's disease (AD), the most common age-related neurodegenerative disorder, is characterized by the accumulation of β-amyloid peptide. In man, [18F]AV-45 with positron emission tomography (PET) is currently studied and used to track in vivo amyloid accumulation. Here, [18F]-AV45-PET was used to visualize amyloid deposition in a transgenic murine model of amyloidosis (APP/PS1-21). Studies were performed ex vivo by autoradiography and in vivo by microPET. Autoradiograms of the brain sections highlighted an increased uptake of [18F]AV-45 in APP/PS1-21 mice compared with age-matched control mice. From 8 months, an intense labeling was observed in cortex, hippocampus, and striatum. The marked accumulation of radiotracer was found in close association with thioflavin S-positive amyloid plaques. The longitudinal microPET assessment, performed from 3 to 12 months of age, demonstrated an increased [18F]AV-45 uptake in APP/PS1-21 compared with control mice. The elevated tracer uptake was increased in association with age. This study opens the possibility of [18F]AV-45, coupled with microPET, to visualize and quantitatively measure amyloid deposits in the brains of living APP/PS1 mice.