Targeting Amyloids with [18F]AV-45 for Medullary Thyroid Carcinoma Positron Emission Tomography/Computed Tomography Imaging: A Pilot Clinical Study.

Medullary thyroid carcinoma (MTC) is a malignant neuroendocrine tumor with a high recurrence rate. Amyloid plaques formed from the misfolding of calcitonin are the key characteristics of MTC. Herein, we conducted a first-in-human pilot clinical study by applying a ß-amyloid-specific radiotracer, [18F]AV-45, to positron emission tomography (PET)/computed tomography (CT) imaging of MTC. The presence of amyloid plaques in the tumor tissue sections from five MTC patients was confirmed by hematoxylin and eosin (H&E) and Congo Red staining. [18F]AV-45 selectively accumulated in the amyloid plaques in the continued tumor tissue sections with similar distribution patterns to the H&E and Congo Red staining. In addition, the [18F]AV-45 uptake can be largely blocked by its nonradioactive reference compound. The [18F]AV-45 accumulation in the thyroid, neck lymph nodes, and muscles in healthy human subjects is close to the background indicated by PET/CT imaging. In the comparison PET/CT imaging study of a recurrent MTC patient, 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG) showed an elevated uptake by multiple neck lymph nodes. In contrast, only one of these neck lymph nodes had increased [18F]AV-45 uptake. Postoperative histopathological analysis confirmed the [18F]AV-45 PET-positive lymph node as MTC with amyloid deposition, while other [18F]FDG positive lymph nodes were free from MTC and amyloid plaques. Thus, [18F]AV-45 showed the promise for the clinical PET/CT imaging of MTC.

18F-FDG PET, the early phases and the delivery rate of 18F-AV45 PET as proxies of cerebral blood flow in Alzheimer's disease: Validation against 15O-H2O PET.

INTRODUCTION: Dual-biomarker positron emission tomography (PET), providing complementary information on cerebral blood flow and amyloid-ß 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.

Improved longitudinal [(18)F]-AV45 amyloid PET by white matter reference and VOI-based partial volume effect correction.

Amyloid positron-emission-tomography (PET) offers an important research and diagnostic tool for investigating Alzheimer's disease (AD). The majority of amyloid PET studies have used the cerebellum as a reference region, and clinical studies have not accounted for atrophy-based partial volume effects (PVE). Longitudinal studies using cerebellum as reference tissue have revealed only small mean increases and high inter-subject variability in amyloid binding. We aimed to test the effects of different reference regions and PVE-correction (PVEC) on the discriminatory power and longitudinal performance of amyloid PET. We analyzed [(18)F]-AV45 PET and T1-weighted MRI data of 962 subjects at baseline and two-year follow-up data of 258 subjects. Cortical composite volume-of-interest (VOI) values (COMP) for tracer uptake were generated using either full brain atlas VOIs, gray matter segmented VOIs or gray matter segmented VOIs after VOI-based PVEC. Standard-uptake-value ratios (SUVR) were calculated by scaling the COMP values to uptake in cerebellum (SUVRCBL), brainstem (SUVRBST) or white matter (SUVRWM). Mean SUV, SUVR, and changes after PVEC were compared at baseline between diagnostic groups of healthy controls (HC; N=316), mild cognitive impairment (MCI; N=483) and AD (N=163). Receiver operating characteristics (ROC) were calculated for the discriminations between HC, MCI and AD, and expressed as area under the curve (AUC). Finally, the longitudinal [(18)F]-AV45-PET data were used to analyze the impact of quantitation procedures on apparent changes in amyloid load over time. Reference region SUV was most constant between diagnosis groups for the white matter. PVEC led to decreases of COMP-SUV in HC (-18%) and MCI (-10%), but increases in AD (+7%). Highest AUCs were found when using PVEC with white matter scaling for the contrast between HC/AD (0.907) or with brainstem scaling for the contrast between HC/MCI (0.658). Longitudinal increases were greatest in all diagnosis groups with application of PVEC, and inter-subject variability was lowest for the white matter reference. Thus, discriminatory power of [(18)F]-AV45-PET was improved by use of a VOI-based PVEC and white matter or brainstem rather than cerebellum reference region. Detection of longitudinal amyloid increases was optimized with PVEC and white matter reference tissue.

Uptake of 18F-AV45 in the Putamen Provides Additional Insights into Alzheimer's Disease beyond the Cortex.

Cortical uptake in brain amyloid positron emission tomography (PET) is increasingly used for the biological diagnosis of Alzheimer's disease (AD); however, the clinical and biological relevance of the striatum beyond the cortex in amyloid PET scans remains unclear. A total of 513 amyloid-positive participants having 18F-AV45 amyloid PET scans available were included in the analysis. The associations between cognitive scores and striatal uptake were analyzed. The participants were categorized into three groups based on the residual from the linear fitting between 18F-AV45 uptake in the putamen and the cortex in the order of HighP > MidP > LowP group. We then examined the differences between these three groups in terms of clinical diagnosis, APOE genotype, CSF phosphorylated tau (ptau) concentration, hippocampal volume, entorhinal thickness, and cognitive decline rate to evaluate the additional insights provided by the putamen beyond the cortex. The 18F-AV45 uptake in the putamen was more strongly associated with ADAS-cog13 and MoCA scores (p < 0.001) compared to the uptake in the caudate nucleus. Despite comparable cortical uptakes, the HighP group had a two-fold higher risk of being ε4-homozygous or diagnosed with AD dementia compared to the LowP group. These three groups had significantly different CSF ptau concentration, hippocampal volume, entorhinal thickness, and cognitive decline rate. These findings suggest that the assessment of 18F-AV45 uptake in the putamen is of unique value for evaluating disease severity and predicting disease progression.

Simple Synthesis of [18F] AV-45 and its Clinical Application in the Diagnosis of Alzheimer's Disease.

OBJECTIVE: [18F] AV-45 can be produced in a simple, stable, and repeatable manner on the Tracerlab FXF-N platform using a self-editing synthetic procedure and solid-phase extraction purification method. This technique is applied to positron emission tomography (PET) imaging of Alzheimer's disease (AD) to observe its distribution and characteristics in various brain regions and its diagnostic efficiency for the disease. METHODS: The precursor was subjected to nucleophilic radiofluorination at 120°C in anhydrous dimethyl sulfoxide, followed by acid hydrolysis of the protecting groups. The neutralized reaction mixture was purified by solid phase extraction to obtain a relatively pure [18F] AV-45 product with a high specific activity. A total of 10 participants who were diagnosed with Alzheimer's disease (AD group) and 10 healthy controls (HC group) were included retrospectively. All of them underwent [18F] AV-45 brain PET/CT imaging. The distribution of [18F] AV-45 in the AD group was analyzed visually and semi-quantitatively. RESULTS: Six consecutive radiochemical syntheses were performed in this experiment. The average production time of [18F] AV-45 was 52 minutes, the radiochemical yield was 14.2 % ± 2.7% (n = 6), and the radiochemical purity was greater than 95%. When used with PET/CT imaging, the results of the visual analysis indicated increased [18F] AV-45 radioactivity uptake in the frontal, temporal, and parietal lobes in AD patients. Semiquantitative analysis showed the highest diagnostic efficacy in the posterior cingulate gyrus compared with other brain regions (P < 0.001). CONCLUSION: Intravenous [18F] AV-45 was successfully prepared on the Tracerlab FXF-N platform by solid-phase extraction of crude product and automated radiochemical synthesis. PET/CT imaging can be used to diagnose and evaluate AD patients and provide a more robust basis for clinicians to diagnose AD.

Preparation and stability of ethanol-free solution of [18F]florbetapir ([18F]AV-45) for positron emission tomography amyloid imaging.

We have developed an ethanol-free formulation method of [(18) F]florbetapir ([(1) (8) F]AV-45) using a commercially available automated JFE multi-purpose synthesizer. We have also evaluated the radiochemical stability in an ethanol-free solution of [(18) F]AV-45 under visible light irradiation and dark conditions by comparison with a conventional 10% ethanol solution of [(18) F]AV-45. [(18) F]AV-45 was obtained with a radiochemical yield of 55.1 ± 2.2% (decay-corrected to end of bombardment), specific activity of 591.6 ± 90.3 GBq/µmol and radiochemical purity of >99% within a total synthesis time of about 73 min. The radiochemical purity of [(18) F]AV-45 formulated by dissolving the ethanol-free solution was found to decrease as a function of the period of exposure to visible light. In contrast, the visible light photolysis could be suppressed by adding 10% ethanol to the formulation or by avoiding exposure to visible light. In the radiosynthesis of [(18) F]AV-45 formulated by dissolving the ethanol-free solution, [(18) F]AV-45 could be obtained with high radiochemical purity and high stability by avoiding exposure to visible light.

Clinical and biological relevance of glial fibrillary acidic protein in Alzheimer's disease.

INTRODUCTION: There is a tremendous need for identifying reliable blood-based biomarkers for Alzheimer's disease (AD) that are tied to the biological ATN (amyloid, tau and neurodegeneration) framework as well as clinical assessment and progression. METHODS: One hundred forty-four elderly participants underwent 18F-AV45 positron emission tomography (PET) scan, structural magnetic resonance imaging (MRI) scan, and blood sample collection. The composite standardized uptake value ratio (SUVR) was derived from 18F-AV45 PET to assess brain amyloid burden, and the hippocampal volume was determined from structural MRI scans. Plasma glial fibrillary acidic protein (GFAP), phosphorylated tau-181 (ptau-181), and neurofilament light (NfL) measured by single molecular array (SIMOA) technology were assessed with respect to ATN framework, genetic risk factor, age, clinical assessment, and future functional decline among the participants. RESULTS: Among the three plasma markers, GFAP best discriminated participants stratified by clinical diagnosis and brain amyloid status. Age was strongly associated with NfL, followed by GFAP and ptau-181 at much weaker extent. Brain amyloid was strongly associated with plasma GFAP and ptau-181 and to a lesser extent with plasma NfL. Moderate association was observed between plasma markers. Hippocampal volume was weakly associated with all three markers. Elevated GFAP and ptau-181 were associated with worse cognition, and plasma GFAP was the most predictive of future functional decline. Combining GFAP and ptau-181 together was the best model to predict brain amyloid status across all participants (AUC = 0.86) or within cognitively impaired participants (AUC = 0.93); adding NfL as an additional predictor only had a marginal improvement. CONCLUSION: Our findings indicate that GFAP is of potential clinical utility in screening amyloid pathology and predicting future cognitive decline. GFAP, NfL, and ptau-181 were moderately associated with each other, with discrepant relevance to age, sex, and AD genetic risk, suggesting their relevant but differential roles for AD assessment. The combination of GFAP with ptau-181 provides an accurate model to predict brain amyloid status, with the superior performance of GFAP over ptau-181 when the prediction is limited to cognitively impaired participants.

Optimization of Automatic Synthesis and Separation of [18F] AV-45 and Quality Control.

Objective: Based on the Tracerlab FXF-N platform, a synthesis program and preparative high-performance liquid chromatography (HPLC) purification program edited by us can stably and repeatedly produce [18F] AV-45 without changing the process. The [18F] AV-45 produced meets the main indexes of radiopharmaceutical intravenous preparations. Methods: The O-toluene sulfonated precursor (1 mg) was subjected to nucleophilic radiofluorination at 115°C in anhydrous dimethyl sulfoxide (DMSO), then the protective group was hydrolyzed by acid. The neutralized reaction mixture was purified through a preparative HPLC then formulated for injection using a C18 purification cartridge. This method yielded a relatively pure [18F] AV-45 product with high specific activity. Results: Four consecutive radiochemical synthesis operations were carried out in this experiment; the average production time of [18F] AV-45 preparation was 60 min, the radiochemical yield was 14.8 ± 2.1% (n = 4), the radiochemical purity was greater than 95%, and the other important quality control indexes met the requirements of radioactive drugs for intravenous administration. Conclusion: This experiment was based on the Tracerlab FXF-N platform with the synthesis program and preparative HPLC purification program edited by us. Through screening and optimization of the separation and purification system and the separation and analysis system, as well as automatic radiochemical synthesis and preparation quality control, intravenous [18F] AV-45 was successfully prepared.

Traumatic brain injury fast-forwards Alzheimer's pathology: evidence from amyloid positron emission tomorgraphy imaging.

PURPOSE: Traumatic brain injury (TBI) has been proposed as a risk factor for Alzheimer's disease (AD), although the mechanisms underlying the putative association are poorly understood. We investigated elderly individuals with a remote history of TBI, aiming to understand how this may have influenced amyloidosis, neurodegeneration, and clinical expression along the AD continuum. METHODS: Total of 241 individual datasets including amyloid beta (Aß) positron emission tomography ([18F]-AV45), structural MRI, and neuropsychological measures, were obtained from the Alzheimer's Disease Neuroimaging Initiative. The data were stratified into groups with (TBI +) or without (TBI -) history of head injury, and by clinical dementia rating (CDR) scores, into subgroups with normal cognition (CDR = 0) and those with symptomatic cognitive decline (CDR ≥ 0.5). We contrasted the TBI + and TBI - subgroups with respect to the onset age and extent of cognitive decline, cortical thickness changes, and Aß standard uptake value (SUVr). RESULTS: Compared to the TBI -/CDR ≥ 0.5 subgroup, the TBI + /CDR ≥ 0.5 subgroup showed a 3-4 year earlier age of cognitive impairment onset (ACIO, p = 0.005). Among those participants on the AD continuum (Aß + , as defined by a cortical SUVr ≥ 1.23), irrespective of current CDR, a TBI + history was associated with greater Aß deposition and more pronounced cortical thinning. When matched for severity of cognitive status, the TBI + /CDR ≥ 0.5 group showed greater Aß burden, but earlier ACIO as compared to the TBI -/CDR ≥ 0.5, suggesting a more indolent clinical AD progression in those with TBI history. CONCLUSION: Remote TBI history may alter the AD onset trajectory, with approximately 4 years earlier ACIO, greater amyloid deposition, and cortical thinning.

Evaluation of the early-phase [18F]AV45 PET as an optimal surrogate of [18F]FDG PET in ageing and Alzheimer's clinical syndrome.

Dual-phase [18F]AV45 positron emission tomography (PET) is highly promising in the assessment of neurodegenerative diseases, allowing to obtain information on both neurodegeneration (early-phase; eAV45) and amyloid deposition (late-phase; lAV45) which are highly complementary; yet eAV45 needs further evaluation. This study aims at validating eAV45 as an optimal proxy of [18F]FDG PET in a large mixed-population of healthy ageing and Alzheimer's clinical syndrome participants (n = 191) who had [18F]FDG PET, eAV45 and lAV45 scans. We found early time frame 0-4 min to give maximal correlation with [18F]FDG PET and minimal correlation with lAV45. Moreover, maximal overlap of [18F]FDG PET versus eAV45 associations with clinical diagnosis and cognition was obtained with pons scaling. Across reference regions, classification performance between clinical subgroups was similar for both eAV45 and [18F]FDG PET. These findings highlight the optimal use of eAV45 to assess neurodegeneration as a validated proxy of [18F]FDG PET. On top of this purpose, this study showed that combined [18F]AV45 PET dual-biomarker even outperformed [18F]FDG PET or lAV45 alone.

Improvement of electroacupuncture on APP/PS1 transgenic mice in behavioral probably due to reducing deposition of Aß in hippocampus.

Alzheimer's disease (AD) is a fatal neurodegenerative disease for which currently no cure is available. Electroacupuncture (EA) has been widely used in China as an alternative therapeutic approach for neurological diseases. The cognitive decline in patients with AD has been reported to be closely related to the deposition of amyloid-ß (Aß) in the hippocampus of the brain, and the Morris water maze (MWM) test is a widely used method for assessing the behavior of animal models. In this study, the MWM test was performed to evaluate the effects of EA treatment on cognitive function and memory, and the micro-positron emission tomography scan was used to assess the hippocampal Aß deposition. The results showed that the cognitive function of APP/PS1 mice was significantly improved and the rate of [18F]AV-45 uptake was reduced in the EA group, compared with the AD group. Our study suggested that EA can exert a therapeutic effect in AD by improving spatial learning and memory and inhibiting the hippocampal Aß deposition.

Associations Between Amyloid and Tau Pathology, and Connectome Alterations, in Alzheimer's Disease and Mild Cognitive Impairment.

BACKGROUND: The roles of amyloid-ß and tau in the degenerative process of Alzheimer's disease (AD) remain uncertain. [18F]AV-45 and [18F]AV-1451 PET quantify amyloid-ß and tau pathology, respectively, while diffusion tractography enables detection of their microstructural consequences. OBJECTIVE: Examine the impact of amyloid-ß and tau pathology on the structural connectome and cognition, in mild cognitive impairment (MCI) and AD. METHODS: Combined [18F]AV-45 and [18F]AV-1451 PET, diffusion tractography, and cognitive assessment in 28 controls, 32 MCI, and 26 AD patients. RESULTS: Hippocampal connectivity was reduced to the thalami, right lateral orbitofrontal, and right amygdala in MCI; alongside the insula, posterior cingulate, right entorhinal, and numerous cortical regions in AD (all p < 0.05). Hippocampal strength inversely correlated with [18F]AV-1451 SUVr in MCI (r = -0.55, p = 0.049) and AD (r = -0.57, p = 0.046), while reductions in hippocampal connectivity to ipsilateral brain regions correlated with increased [18F]AV-45 SUVr in those same regions in MCI (r = -0.33, p = 0.003) and AD (r = -0.31, p = 0.006). Cognitive scores correlated with connectivity of the right temporal pole in MCI (r = -0.60, p = 0.035) and left hippocampus in AD (r = 0.69, p = 0.024). Clinical Dementia Rating Scale scores correlated with [18F]AV-1451 SUVr in multiple areas reflecting Braak stages I-IV, including the right (r = 0.65, p = 0.004) entorhinal cortex in MCI; and Braak stages III-VI, including the right (r = 0.062, p = 0.009) parahippocampal gyrus in AD. CONCLUSION: Reductions in hippocampal connectivity predominate in the AD connectome, correlating with hippocampal tau in MCI and AD, and with amyloid-ß in the target regions of those connections. Cognitive scores correlate with microstructural changes and reflect the accumulation of tau pathology.

Exploring the Pattern Associated With Longitudinal Changes of ß-Amyloid Deposition During Cognitively Normal Healthy Aging.

The aim of this study was to determine a pattern associated with longitudinal changes of ß-amyloid (Aß) deposition during cognitively normal(CN) healthy aging. We used 18F-florbetapir (AV-45) PET images of the brains of 207 cognitively normal subjects (CN1), obtained through the Alzheimer's Disease Neuroimaging Initiative (ADNI), to identify the healthy aging pattern and 76 cognitively normal healthy subjects (CN2), obtained through the Xuanwu Hospital of Capital Medical University, Beijing, China, to verify it. A voxel-based correlation analysis of standardized uptake value ratio (SUVR) map image and age was conducted using the DPABI (Data Processing & Analysis of Brain Imaging) software to identify the pattern. The sum of squares due to errors (SSE), R-square (R2) and the root-mean-square error (RMSE) were calculated to assess the quality of curve fitting. Among them, R2 was proposed as the coherence coefficient, which was as an index to assess the correlation between SUVR value of the pattern and subjects' age. The pattern characterized by age-associated longitudinal changes of Aß deposition was mainly distributed in the right middle and inferior temporal gyrus, the right temporal pole: middle temporal gyrus, the right inferior occipital gyrus, the right inferior frontal gyrus (triangular portion), and the right precentral gyrus. There were a significant positive correlation between the SUVR value of the pattern and age for each CN group (CN1: R2 = 0.120, p < 0.001 for quadratic model; CN2: R2 = 0.152, p = 0.002 for quadratic model). These findings suggest a pattern of changes in Aß deposition that can be used to distinguish physiological changes from pathophysiological changes, constituting a new method for elucidating the neuropathological mechanism of Alzheimer's disease.

Biomarker Localization, Analysis, Visualization, Extraction, and Registration (BLAzER) Methodology for Research and Clinical Brain PET Applications.

BACKGROUND: Tools for efficient evaluation of amyloid- and tau-PET images are needed in both clinical and research settings. OBJECTIVE: This study was designed to validate a semi-automated image analysis methodology, called Biomarker Localization, Analysis, Visualization, Extraction, and Registration (BLAzER). We tested BLAzER using two different segmentation platforms, FreeSurfer (FS) and Neuroreader (NR), for regional brain PET quantification in participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. METHODS: 127 amyloid-PET and 55 tau-PET studies with volumetric MRIs were obtained from ADNI. The BLAzER methodology utilizes segmentation of MR images by FS or NR, then visualizes and quantifies regional brain PET data using FDA-cleared software (MIM), enabling quality control to ensure optimal registration and to detect segmentation errors. RESULTS: BLAzER analysis required ∼5 min plus segmentation time. BLAzER using FS segmentation showed strong agreement with ADNI for global amyloid-PET standardized uptake value ratios (SUVRs) (r = 0.9922, p < 0.001) and regional tau-PET SUVRs across all Braak staging regions (r > 0.97, p < 0.001) with high inter-operator reproducibility (ICC > 0.97) and nearly identical dichotomization as amyloid-positive or -negative (2 discrepant cases out of 127). Comparing FS versus NR segmentation with BLAzER, global SUVRs were strongly correlated for amyloid-PET (r = 0.9841, p < 0.001), but were systematically higher (4% on average) with NR, likely due to more inclusion of white matter with NR-defined regions. CONCLUSIONS: BLAzER provides an efficient methodology for regional brain PET quantification. FDA-cleared components and visualization of registration reduce barriers between research and clinical applications.

Tau PET With 18F-THK-5351 Taiwan Patients With Familial Alzheimer's Disease With the APP p.D678H Mutation.

Background: Brain 18F-AV-45 amyloid positron emission tomography (PET) in Taiwanese patients with familial Alzheimer's disease with the amyloid precursor protein (APP) p.D678H mutation tends to involve occipital and cerebellar cortical areas. However, tau pathology in patients with this specific Taiwan mutation remains unknown. In this study, we aimed to study the Tau PET images in these patients. Methods: Clinical features, brain magnetic resonance imaging/computed tomography (MRI/CT), and brain 18F-THK-5351 PET were recorded in five patients with the APP p.D678H mutation and correlated with brain 18F-AV-45 PET images. We also compared the tau deposition patterns among five patients with familial mild cognitive impairment (fMCI), six patients with sporadic amnestic mild cognitive impairment (sMCI), nine patients with mild to moderate dementia due to Alzheimer's disease (AD), and 12 healthy controls (HCs). All of the subjects also received brain 18F-AV-45 PET. Results: The nine patients with sAD and six patients with sMCI had a positive brain AV-45 PET scans, while the 12 HCs had negative brain AV-45 PET scans. All five patients with fMCI received a tau PET scan with the age at onset ranging from 46 to 53 years, in whom increased standard uptake value ratio (SUVR) of 18F-THK-5351 was noted in all seven brain cortical areas compared with the HCs. In addition, the SUVRs of 18F-THK-5351 were increased in the frontal, medial parietal, lateral parietal, lateral temporal, and occipital areas (P < 0.001) in the patients with sAD compared with the HCs. The patients with fMCI had a significant higher SUVR of 18F-THK-5351 in the cerebellar cortex compared to the patients with sMCI. The correlations between regional SUVR and Mini-Mental State Examination score and between regional SUVR and clinical dementia rating (sum box) scores within volumes of interest of Braak stage were statistically significant. Conclusion: Tau deposition was increased in the patients with fMCI compared to the HCs. Increased regional SUVR in the cerebellar cortical area was a characteristic finding in the patients with fMCI. As compared between amyloid and tau PET, the amyloid deposition is diffuse, but tau deposition is limited to the temporal lobe in the patients with fMCI.

Validation of the Semiquantitative Static SUVR Method for 18F-AV45 PET by Pharmacokinetic Modeling with an Arterial Input Function.

Increased brain uptake of 18F-AV45 visualized by PET is a key biomarker for Alzheimer disease (AD). The SUV 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, 15 amnestic mild cognitive impairment (aMCI), and 10 cognitively healthy controls (HCs). 18F-AV45 VT was determined from 2-tissue-compartment modeling using a metabolite-corrected plasma input function. Static SUVR was calculated at 50-60 min after injection, using either cerebellar gray matter (SUVRCB) or whole subcortical white matter (SUVRWM) as the 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 ± SEM. Results: There was rapid metabolization of 18F-AV45, with only 35% of unchanged parent remaining at 10 min. Compared with VT, differences in cortical Aß load between aMCI and AD were overestimated by SUVRWM (+4% ± 2%) and underestimated by SUVRCB (-10% ± 2%). VT correlated better with SUVRWM (Pearson r: from 0.63 for posterior cingulate to 0.89 for precuneus, P < 0.0001) than with SUVRCB (Pearson 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 with 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 Aß load. However, SUVRWM is better correlated with VT and more closely reflects VT differences between aMCI and AD than SUVRCB.

Longitudinal Characterization of [18F]-FDG and [18F]-AV45 Uptake in the Double Transgenic TASTPM Mouse Model.

We aimed to monitor the timing of amyloid-ß deposition in relation to changes in brain function using in vivo imaging with [18F]-AV45 and [18F]-FDG in a mouse model of Alzheimer's disease. TASTPM transgenic mice and wild-type controls were scanned longitudinally with [18F]-AV45 and [18F]-FDG before (3 months of age) and at multiple time points after the onset of amyloid deposition (6, 9, 12, and 15 months of age). As expected with increasing amyloidosis, TASTPM mice demonstrated progressive age-dependent increases in [18F]-AV45 uptake that were significantly higher than for WT from 9 months onwards and correlated to ex vivo measures of amyloid burden. The metabolism of [18F]-AV45 produces several brain penetrant radiometabolites and normalization to a reference region helps to negate this non-specific binding and improve the sensitivity of [18F]-AV45. The observed trajectory of [18F]-FDG alterations deviated from our proposed hypothesis of gradual decreases with worsening amyloidosis. While [18F]-FDG uptake in TASTPM mice was significantly lower than that of WT at 9 months, reduced [18F]-FDG was not associated with aging in TASTPM mice. Moreover, [18F]-FDG uptake did not correlate to measures of ex vivo amyloid burden. Our findings suggest that while amyloid-ß is sufficient to induce hypometabolism, these pathologies are not linked in a dose-dependent manner in TASTPM mice.

The Cerebrospinal Fluid Aß1-42/Aß1-40 Ratio Improves Concordance with Amyloid-PET for Diagnosing Alzheimer's Disease in a Clinical Setting.

BACKGROUND: Evidence suggests that the concordance between amyloid-PET and cerebrospinal fluid (CSF) amyloid-ß (Aß) increases when the CSF Aß1-42/Aß1-40 ratio is used as compared to CSF Aß1-42 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 [18F]Florbetapir ([18F]AV45) PET scan, [18F]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 (Aß1-42, Aß1-40, T-tau, P-tau181). RESULTS: We detected an increased concordance in the visual and quantitative (standardized uptake value ratio (SUVR) and total volume of distribution (VT)) [18F]AV45 PET measures when the CSF Aß1-42/Aß1-40 was applied compared to Aß1-42 alone. CSF biomarkers were stronger associated to [18F]AV45 PET for SUVR values when considering the total brain white matter as reference region instead of cerebellar grey matterConclusions:The concordance between CSF Aß and [18F]AV45 PET increases when the CSF Aß1-42/Aß1-40 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.