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1.  Neuropathologic Heterogeneity Does Not Impair Florbetapir-PET Postmortem Correlates 
Neuropathologic heterogeneity is often present within Alzheimer’s disease (AD). We sought to determine if amyloid imaging measures of AD are affected by concurrent pathologies. Thirty-eight clinicopathologically-defined AD and 17 non-demented cases (ND) with quantitative florbetapir F-18 (18F-AV-45) PET imaging during life and histological β-amyloid quantification and neuropathologic examination were assessed. AD cases were divided on the basis of concurrent pathologies, including those with Lewy bodies (N=21), white matter rarefaction (N=27), severe cerebral amyloid angiopathy (N=11), argyrophilic grains (N=5) and TDP-43 inclusions (N=18). Many cases exhibited more than one type of concurrent pathology. The ratio of cortical to cerebellar amyloid imaging signal (SUVr) and immunohistochemical β-amyloid load were analyzed in six cortical regions of interest. All AD subgroups had strong and significant correlations between SUVr and histological β-amyloid measures (p values <0.001). All AD subgroups had significantly greater amyloid measures compared to ND, and mean amyloid measures did not significantly differ between AD subgroups. When comparing AD cases with and without each pathology, AD cases with Lewy bodies had significantly decreased SUVr measures compared to AD cases without (p = 0.002); there were no other paired comparison differences. These findings indicate florbetapir-PET imaging is not confounded by neuropathological heterogeneity within AD.
doi:10.1097/NEN.0000000000000028
PMCID: PMC4037918  PMID: 24335535
argyrophilic grains; autopsy; cerebral amyloid angiopathy; Lewy bodies; plaques; TDP-43; vascular dementia; white matter; leuko-araiosis
2.  Comparing PET imaging and CSF measurements of Aβ 
Annals of neurology  2013;74(6):826-836.
Objective
We examined agreement and disagreement between two biomarkers of Aβ deposition (amyloid PET and CSF Aβ1-42) in normal aging and dementia in a large multicenter study.
Methods
Concurrently acquired florbetapir-PET and CSF Aβ were measured in cognitively normal, mild cognitive impairment (MCI), and Alzheimer’s disease (AD) participants (N=374) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). We also compared Aβ measurements in a separate group with serial CSF measurements over 3.1 +/− 0.8 yrs that preceded a single florbetapir session. Additional biomarker and cognitive data allowed us to further examine profiles of discordant cases.
Results
Florbetapir and CSF Aβ were inversely correlated across all diagnostic groups, and dichotomous measurements were in agreement in 86% of subjects. Among subjects showing the most disagreement, the two discordant groups had different profiles: the florbetapir+/CSF Aβ− group was larger (N=13) and was made up of only normal and early MCI subjects; while the florbetapir−/CSF Aβ+ group was smaller (N=7), had poorer cognitive function and higher CSF tau, but no ApoE4 carriers. In the longitudinal sample, we observed both stable longitudinal CSF Aβ trajectories and those actively transitioning from normal to abnormal, but the final CSF Aβ measurements were in good agreement with florbetapir cortical retention.
Interpretation
CSF and amyloid-PET measurements of Aβ were consistent in the majority of subjects in the cross-sectional and longitudinal populations. Based on our analysis of discordant subjects, the available evidence did not show that CSF Aβ regularly becomes abnormal prior to fibrillar Aβ accumulation early in the course of disease.
doi:10.1002/ana.23908
PMCID: PMC3748164  PMID: 23536396
3.  Positive Florbetapir PET Amyloid Imaging in a Subject with Frequent Cortical Neuritic Plaques and Frontotemporal Lobar Degeneration with TDP43-Positive Inclusions 
Abnormal neuronal accumulation and modification of TAR DNA binding protein 43 (TDP-43) have recently been discovered to be defining histopathological features of particular subtypes of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), and are also common in aging, particularly coexisting with hippocampal sclerosis and Alzheimer's disease (AD) pathology. This case report describes a 72 year old Hispanic male with no family history of neurological disease, who presented at age 59 with obsessive behavior, anxiety, agitation and dysphasia. Positron emission tomography (PET) imaging using the amyloid ligand 18F florbetapir (Amyvid) was positive. Postmortem examination revealed frequent diffuse and neuritic amyloid plaques throughout the cerebral cortex, thalamus and striatum, Braak stage II neurofibrillary degeneration and frequent frontal and temporal cortex TDP-43-positive neurites with rare nuclear inclusions. The case is unusual and instructive because of the co-existence of frequent cortical and diencephalic amyloid plaques with extensive TDP-43-positive histopathology in the setting of early-onset dementia and because it demonstrates that a positive cortical amyloid imaging signal in a subject with dementia does not necessarily establish that AD is the sole cause.
doi:10.3233/JAD-140162
PMCID: PMC4167919  PMID: 24927705
Alzheimer's disease; frontotemporal dementia; neurofibrillary degeneration; neuritic amyloid plaques
4.  PET imaging of amyloid with Florbetapir F 18 and PET imaging of dopamine degeneration with 18F-AV-133 (florbenazine) in patients with Alzheimer’s disease and Lewy body disorders 
BMC Neurology  2014;14:79.
Background
Biomarkers based on the underlying pathology of Alzheimer’s disease (AD) and Dementia with Lewy Bodies (DLB) have the potential to improve diagnosis and understanding of the substrate for cognitive impairment in these disorders. The objective of this study was to compare the patterns of amyloid and dopamine PET imaging in patients with AD, DLB and Parkinson’s disease (PD) using the amyloid imaging agent florbetapir F 18 and 18F-AV-133 (florbenazine), a marker for vesicular monamine type 2 transporters (VMAT2).
Methods
Patients with DLB and AD, Parkinson’s disease (PD) and healthy controls (HC) were recruited for this study. On separate days, subjects received intravenous injections of florbetapir, and florbenazine. Amyloid burden and VMAT2 density were assessed quantitatively and by binary clinical interpretation. Imaging results for both tracers were compared across the four individual diagnostic groups and for combined groups based on underlying pathology (AD/DLB vs. PD/HC for amyloid burden and PD/DLB vs. AD/HC for VMAT binding) and correlated with measures of cognition and parkinsonism.
Results
11 DLB, 10 AD, 5 PD, and 5 controls participated in the study. Amyloid binding was significantly higher in the combined AD/DLB patient group (n = 21) compared to the PD/HC groups (n = 10, mean SUVr: 1.42 vs. 1.07; p = 0.0006). VMAT2 density was significantly lower in the PD/DLB group (n = 16) compared to the AD/ HC group (n = 15; 1.83 vs. 2.97; p < 0.0001). Within the DLB group, there was a significant correlation between cognitive performance and striatal florbenazine binding (r = 0.73; p = 0.011).
Conclusions
The results of this study show significant differences in both florbetapir and florbenazine imaging that are consistent with expected pathology. In addition, VMAT density correlated significantly with cognitive impairment in DLB patients (ClinicalTrials.gov identifier: NCT00857506, registered March 5, 2009).
doi:10.1186/1471-2377-14-79
PMCID: PMC4027995  PMID: 24716655
PET imaging; Alzheimer’s disease; Parkinson’s disease; Biomarkers
5.  Amyloid deposition detected with florbetapir F 18 (18F-AV-45) is related to lower episodic memory performance in clinically normal older individuals 
Neurobiology of aging  2012;34(3):822-831.
The objective of this study was to evaluate the relationship of amyloid burden, as assessed by florbetapir F 18 (18F-AV-45) amyloid PET, and cognition in healthy older control subjects (HC). Seventy-eight HC subjects were assessed with a brief cognitive test battery and PET imaging with florbetapir F 18. A standard uptake value ratio (SUVr) was computed for mean data from six cortical regions using a whole cerebellum reference region. Scans were also visually rated as amyloid positive (Aβ+) or amyloid negative (Aβ−) by three readers. Higher SUVr correlated with lower immediate memory (r=−0.33; p=0.003) and delayed recall scores (r=−0.25; p=0.027). Performance on immediate recall was also lower in the visually rated Aβ+ compared to Aβ− HC (p=0.04), with a similar trend observed in delayed recall (p=0.06). These findings support the hypothesis that higher amyloid burden is associated with lower memory performance among clinically normal older subjects. Longitudinal follow-up is ongoing to determine whether florbetapir F 18 may also predict subsequent cognitive decline.
doi:10.1016/j.neurobiolaging.2012.06.014
PMCID: PMC3518678  PMID: 22878163
6.  Amyloid imaging and cognitive decline in non-demented oldest-old: The 90+ Study 
Background
The goal of this study was to examine cross-sectional and longitudinal associations between cognitive performance and beta amyloid (Aβ) load determined by florbetapir F18 positron emission tomography (PET) in non-demented oldest-old.
Methods
Thirteen non-demented (normal or cognitively impaired non-demented) participants (median age=94.2 years) from The 90+ Study underwent florbetapir-PET scanning within 3 months of baseline neuropsychological testing. Amyloid load was measured with a semiautomated quantitative analysis of average cortical to cerebellar standard uptake values (SUVr) ratio and a visual interpretation (Aβ- or Aβ+). Neuropsychological testing was repeated every 6 months.
Results
At baseline, SUVr correlated significantly with tests of global cognition and memory. During follow-up (median=1.5 years), the Aβ+ group had steeper declines on most cognitive tests, particularly global cognitive measures.
Conclusion
This preliminary study suggests that greater amyloid load is associated with poorer cognition and faster cognitive decline in non-demented oldest-old. Amyloid load may identify individuals at increased risk of developing Alzheimer's disease.
doi:10.1016/j.jalz.2012.06.005
PMCID: PMC3604036  PMID: 23164550
7.  Radiation dosimetry of florbetapir F 18 
EJNMMI Research  2014;4:4.
Background
Florbetapir is one of several 18F-labeled amyloid plaque imaging tracers for positron emission tomography (PET). As the bio-distribution and radiation dose of PET tracers in human research are important for estimating the relative risks and benefits, a study was conducted to obtain this information on florbetapir.
Methods
Nine cognitively normal subjects (six females and three males, age 58 ± 10 years, weight 81 ± 17 kg) received an intravenous bolus injection of 395 ± 27.9 MBq of florbetapir, and whole-body emission scans were performed over approximately 6 h. Computed tomography scans were acquired for attenuation correction. Volumes of interest (VOIs) for source organs including the brain, liver, lung, heart wall, and vertebrae were defined on the PET images. The VOIs of the gallbladder, urinary bladder, and large and small intestines were also defined. Using reference man organ volumes (ICRP 30), total activity was calculated per organ for each time point. The resultant time-activity curves (TACs) were fitted with constrained exponentials. Kinetic data were entered into OLINDA/EXM software to calculate dose estimates; the dynamic urinary bladder and ICRP 30 GI tract models were employed. The effective dose (ED) for each subject was estimated from the acquired data using the adult model.
Results
The mean ED determined for nine healthy volunteers was 18.60 ± 4.26 μSv/MBq or 6.88 mSv for a 370-MBq dose. The organs that received the highest radiation absorbed doses were the gallbladder, upper large intestine, small intestine, liver, and urinary bladder at 143.0 ± 80.20, 74.50 ± 34.20, 65.50 ± 29.60, 64.40 ± 22.10, and 27.10 ± 11.70 μSv/MBq, respectively.
Conclusions
The ED for florbetapir has been calculated for nine healthy volunteers. At a dose of 370 MBq florbetapir, the total average ED is approximately 6.88 mSv.
doi:10.1186/2191-219X-4-4
PMCID: PMC4061749  PMID: 24401181
8.  Amyloid-β assessed by florbetapir F 18 PET and 18-month cognitive decline 
Neurology  2012;79(16):1636-1644.
Objectives:
Florbetapir F 18 PET can image amyloid-β (Aβ) aggregates in the brains of living subjects. We prospectively evaluated the prognostic utility of detecting Aβ pathology using florbetapir PET in subjects at risk for progressive cognitive decline.
Methods:
A total of 151 subjects who previously participated in a multicenter florbetapir PET imaging study were recruited for longitudinal assessment. Subjects included 51 with recently diagnosed mild cognitive impairment (MCI), 69 cognitively normal controls (CN), and 31 with clinically diagnosed Alzheimer disease dementia (AD). PET images were visually scored as positive (Aβ+) or negative (Aβ−) for pathologic levels of β-amyloid aggregation, blind to diagnostic classification. Cerebral to cerebellar standardized uptake value ratios (SUVr) were determined from the baseline PET images. Subjects were followed for 18 months to evaluate changes in cognition and diagnostic status. Analysis of covariance and correlation analyses were conducted to evaluate the association between baseline PET amyloid status and subsequent cognitive decline.
Results:
In both MCI and CN, baseline Aβ+ scans were associated with greater clinical worsening on the Alzheimer's Disease Assessment Scale–Cognitive subscale (ADAS-Cog (p < 0.01) and Clinical Dementia Rating–sum of boxes (CDR-SB) (p < 0.02). In MCI Aβ+ scans were also associated with greater decline in memory, Digit Symbol Substitution (DSS), and Mini-Mental State Examination (MMSE) (p < 0.05). In MCI, higher baseline SUVr similarly correlated with greater subsequent decline on the ADAS-Cog (p < 0.01), CDR-SB (p < 0.03), a memory measure, DSS, and MMSE (p < 0.05). Aβ+ MCI tended to convert to AD dementia at a higher rate than Aβ− subjects (p < 0.10).
Conclusions:
Florbetapir PET may help identify individuals at increased risk for progressive cognitive decline.
doi:10.1212/WNL.0b013e3182661f74
PMCID: PMC3468774  PMID: 22786606
9.  Amyloid-β Imaging with Pittsburgh Compound B and Florbetapir: Comparing Radiotracers and Quantification Methods 
11C-Pittsburgh compound B (11C-PiB) and 18F-florbetapir amyloid-β (Aβ) PET radioligands have had a substantial impact on Alzheimer disease research. Although there is evidence that both radioligands bind to fibrillar Aβ in the brain, direct comparisons in the same individuals have not been reported. Here, we evaluated PiB and florbetapir in a retrospective convenience sample of cognitively normal older controls, patients with mild cognitive impairment, and patients with Alzheimer disease from the Alzheimer’s Disease Neuroimaging Initiative (ADNI).
Methods
From the ADNI database, 32 participants were identified who had undergone at least 1 PiB study and subsequently underwent a florbetapir study approximately 1.5 y after the last PiB study. Cortical PiB and florbetapir retention was quantified using several different methods to determine the effect of preprocessing factors (such as smoothing and reference region selection) and image processing pipelines.
Results
There was a strong association between PiB and florbetapir cortical retention ratios (Spearman ρ = 0.86–0.95), and these were slightly lower than cortical retention ratios for consecutive PiB scans (Spearman ρ = 0.96–0.98) made approximately 1.1 y apart. Cortical retention ratios for Aβ-positive subjects tended to be higher for PiB than for florbetapir images, yielding slopes for linear regression of florbetapir against PiB of 0.59–0.64. Associations between consecutive PiB scans and between PiB and florbetapir scans remained strong, regardless of processing methods such as smoothing, spatial normalization to a PET template, and use of reference regions. The PiB–florbetapir association was used to interconvert cutoffs for Aβ positivity and negativity between the 2 radioligands, and these cutoffs were highly consistent in their assignment of Aβ status.
Conclusion
PiB and florbetapir retention ratios were strongly associated in the same individuals, and this relationship was consistent across several data analysis methods, despite scan–rescan intervals of more than a year. Cutoff thresholds for determining positive or negative Aβ status can be reliably transformed from PiB to florbetapir units or vice versa using a population scanned with both radioligands.
doi:10.2967/jnumed.112.109009
PMCID: PMC3747730  PMID: 23166389
amyloid-β; Alzheimer’s disease; PET imaging
10.  Positron Emission Tomography and Neuropathologic Estimates of Fibrillar Amyloid-β in a Patient With Down Syndrome and Alzheimer Disease 
Archives of Neurology  2011;68(11):1461-1466.
Background
Down syndrome appears to be associated with a virtually certain risk of fibrillar amyloid-β (Aβ) pathology by the age of 40 and a very high risk of dementia at older ages. The positron emission tomography (PET) ligand florbetapir F18 has been shown to characterize fibrillar Aβ in the living human brain and to provide a close correlation with subsequent Aβ neuropathology in individuals proximate to and after the end of life. The extent to which the most frequently used PET ligands can be used to detect fibrillar Aβ in patients with Down syndrome remains to be determined.
Objectives
To characterize PET estimates of fibrillar Aβ burden in a Down syndrome patient very close to the end of life and to compare them with neuropathologic assessment made after his death.
Design/Methods
With the family’s informed consent, florbetapir PET was used to study a 55-year-old Down syndrome patient with Alzheimer disease near the end of life; his brain was donated for neuropathologic assessment when he died 14 days later. Visual ratings of cerebral florbetapir uptake were performed by trained readers who were masked to the patient’s diagnosis as part of a larger study, and an automated algorithm was used to characterize regional-to-cerebellar standard uptake value ratios in 6 cerebral regions of interest. Neuropathologic assessments were performed masked to the patient’s diagnosis or PET measurements.
Results
Visual ratings and automated analyses of the PET image revealed a heavy fibrillar Aβ burden in cortical, striatal, and thalamic regions, similar to that reported for patients with late-onset Alzheimer disease. This matched neuropathologic findings of frequent neuritic and diffuse plaques, as well as frequent amyloid angiopathy, except for neuropathologically demonstrated frequent cerebellar diffuse plaques and amyloid angiopathy that were not detected by the PET scan.
Conclusions
Florbetapir PET can be used to detect increased cerebral-to-cerebellar fibrillar Aβ burden in a Down syndrome patient with Alzheimer disease, even in the presence of frequent amyloid angiopathy and diffuse plaques in the cerebellum. Additional studies are needed to determine the extent to which PET could be used to detect and to track fibrillar Aβ and to evaluate investigational Aβ-modifying treatments in the presymptomatic and symptomatic stages of Alzheimer disease.
doi:10.1001/archneurol.2011.535
PMCID: PMC3346179  PMID: 22084131
11.  PET amyloid imaging as a tool for early diagnosis and identifying patients at risk for progression to Alzheimer's disease 
Current theory suggests that β-amyloid accumulation may be an early step in the cascade that leads to cognitive impairment in Alzheimer's disease. β-Amyloid targeted positron emission tomography (PET) imaging potentially provides a direct, relatively noninvasive estimate of brain β-amyloid burden. This has recently been supported by demonstration that amyloid plaque binding on PET was strongly correlated with brain β-amyloid burden at autopsy. Additionally, there is growing consensus that PET imaging can identify subjects with elevated β-amyloid burden, even at early stages of disease. Finally, preliminary evidence suggests that abnormal β-amyloid accumulation, as evidenced by PET imaging, has implications for both present nd future cognitive performance. Although large longitudinal studies like the ongoing ADNI trial will be required for definitive evaluation, present data suggest that PET amyloid imaging has the potential to promote earlier and more specific diagnosis of dementia.
doi:10.1186/alzrt70
PMCID: PMC3226273  PMID: 21457498
12.  In Vivo Imaging of Amyloid Deposition in Alzheimer’s Disease using the Novel Radioligand [18F]AV-45 (Florbetapir F 18) 
Introduction
An [18F] labeled PET amyloid (Aβ) imaging agent could facilitate clinical evaluation of late-life cognitive impairment by providing an objective measure for Alzheimer’s disease (AD) pathology. Here we present the results of the first clinical trial with [18F]AV-45 (Florbetapir F 18).
Methods
An open-label, multicenter, brain imaging, metabolism and safety study of [18F]AV-45 was performed on 16 patients with Alzheimer’s disease (AD: MMSE 19.3 +/− 3.1; Age 75.8 +/− 9.2) and 16 cognitively healthy controls (HC: MMSE 29.8 +/− 0.45; Age 72.5 +/− 11.6 ). Dynamic PET imaging was performed over a period of approximately 90 minutes following 10 mCi injection of the tracer. Standard uptake values (SUV) and cortical to cerebellum SUV ratios (SUVR) were calculated. A simplified reference tissue method was used to generate distribution volume ratio (DVR) parametric maps in a subset of subjects
Results
Valid PET imaging data were available for 11 AD and 15 HC subjects [18F]AV-45 accumulated in cortical regions expected to be high in amyloid deposition (e.g., precuneus, frontal and temporal cortex) of AD patients; minimal accumulation of tracer was seen in cortical regions of HC subjects. The cortical to cerebellar SUVR values in AD patients showed continual substantial increases through 30 minutes post-administration, reaching a plateau within 50 minutes. The 10 minute period from 50–60 minutes post administration was taken as a representative sample for further analysis. The cortical average SUVR for this period was 1.67 +/− 0.175 for patients with AD vs. 1.25 +/− 0.177 for HC subjects. Spatially normalized DVRs generated from PET dynamic scans were highly correlated with SUVR (r= 0.58–0.88, p<0.005) and were significantly greater for AD patients than for HC subjects in cortical regions, but not in subcortical white matter or cerebellar regions.
There were no clinically significant changes in vital signs, ECG or laboratory values.
Conclusions
[18F]AV-45 was well tolerated and PET imaging showed significant discrimination between AD patients and HC subjects using either a parametric reference region method (DVR) or a simplified SUVR calculated from 10 minutes of scanning 50–60 minutes after [18F]AV-45 administration.
doi:10.2967/jnumed.109.069088
PMCID: PMC3101877  PMID: 20501908
Amyloid; PET; Alzheimer’s Disease; Dementia; Biomarkers; Aging; F-18

Results 1-12 (12)