Florbetapir Positron Emission Tomography Scans Research Articles

Hearing, β-Amyloid Deposition and Cognitive Test Performance in Black and White Older Adults: The ARIC-PET Study.

Hearing loss is a risk factor for dementia; whether the association is causal or due to a shared pathology is unknown. We estimated the association of brain β-amyloid with hearing, hypothesizing no association. As a positive control, we quantified the association of hearing loss with neurocognitive test performance. Cross-sectional analysis of Atherosclerosis Risk in Communities-Positron Emission Tomography study data. Amyloid was measured using global cortical and temporal lobe standardized uptake value ratios (SUVRs) calculated from florbetapir-positron emission tomography scans. Composite global and domain-specific cognitive scores were created from 10 neurocognitive tests. Hearing was measured using an average of better-ear air conduction thresholds (0.5-4 kHz). Multivariable-adjusted linear regression estimated mean differences in hearing by amyloid and mean differences in cognitive scores by hearing, stratified by race. In 252 dementia-free adults (72-92 years, 37% Black race, and 61% female participants), cortical or temporal lobe SUVR was not associated with hearing (models adjusted for age, sex, education, and APOE ε4). Each 10 dB HL increase in hearing loss was associated with a 0.134 standard deviation lower mean global cognitive factor score (95% CI: -0.248, -0.019), after adjustment for demographic and cardiovascular factors. Observed hearing-cognition associations were stronger in Black versus White participants. Amyloid is not associated with hearing, suggesting that pathways linking hearing and cognition are independent of this pathognomonic Alzheimer's-related brain change. This is the first study to show that the impact of hearing loss on cognition may be stronger in Black versus White adults.

Annualized changes in rate of amyloid deposition and neurodegeneration are greater in participants who become amyloid positive than those who remain amyloid negative

This study longitudinally examined participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) who underwent a conversion in amyloid-beta (Aβ) status in comparison to a group of ADNI participants who did not show a change in amyloid status over the same follow-up period. Participants included 136 ADNI dementia-free participants with 2 florbetapir positron emission tomography (PET) scans. Of these participants, 68 showed amyloid conversion as measured on florbetapir PET, and the other 68 did not. Amyloid converters and non-converters were chosen to have representative demographic data (age, education, sex, diagnostic status, and race). The amyloid converter group showed increased prevalence of APOE ε4 (p < 0.001), greater annualized percent volume loss in selected magnetic resonance imaging (MRI) regions (p < 0.05), lower cerebrospinal fluid Aβ1–42 (p < 0.001), and greater amyloid retention (as measured by standard uptake value ratios) on florbetapir PET scans (p < 0.001) in comparison to the non-converter group. These results provide compelling evidence that important neuropathological changes are occurring alongside amyloid conversion.

Rapid Eye Movement Sleep, Neurodegeneration, and Amyloid Deposition in Aging.

Rapid eye movement (REM) sleep is markedly altered in Alzheimer's disease (AD), and its reduction in older populations is associated with AD risk. However, little is known about the underlying brain mechanisms. Our objective was to investigate the relationships between REM sleep integrity and amyloid deposition, gray matter volume, and perfusion in aging. We included 121 cognitively unimpaired older adults (76 women, mean age 68.96 ± 3.82 years), who underwent a polysomnography, T1-weighted magnetic resonance imaging, early and late Florbetapir positron emission tomography scans to evaluate gray matter volume, perfusion, and amyloid deposition. We computed indices reflecting REM sleep macro- and microstructural integrity (ie, normalized electroencephalographic spectral power values). Voxel-wise multiple regression analyses were conducted between REM sleep indices and neuroimaging data, controlling for age, sex, education, the apnea-hypopnea index, and the apolipoprotein E ε4 status. Lower perfusion in frontal, anterior and posterior cingulate, and precuneus areas was associated with decreased delta power and electroencephalographic slowing (slow/fast frequencies ratio), and increased alpha and beta power. To a lower extent, similar results were obtained between gray matter volume and delta, alpha, and beta power. In addition, lower REM sleep theta power was more marginally associated with greater diffuse amyloid deposition and lower gray matter volume in fronto-temporal and parieto-occipital areas. These results suggest that alterations of REM sleep microstructure are associated with greater neurodegeneration and neocortical amyloid deposition in older adults. Further studies are warranted to replicate these findings, and determine whether older adults exhibiting REM sleep alterations are more at risk of cognitive decline and belonging to the Alzheimer's continuum. ANN NEUROL 2023;93:979-990.

Longitudinal Changes in P3 Event‐related Potential among Older Adults with Preclinical Alzheimer’s Disease: A 1‐year Follow‐Up

AbstractBackgroundThe third positive peak of the event‐related potential (ERP P3) is understood to reflect neural resource utilization during working memory. We previously showed lower P3 ERP amplitude of the task effect in older adults with preclinical Alzheimer’s disease (AD). The aim of this study was to compare changes from baseline to 1‐year follow‐up in P3 ERP between older adults with and without preclinical AD.MethodCognitively normal, beta‐amyloid positive (CNAβ+, n = 14) participants and beta‐amyloid negative (CNAβ‐, n = 15) controls completed a working memory task (n‐back) with three levels of difficulty (0, 1, 2) at baseline and 1‐year follow‐up. ERP P3 peak amplitude and latency of the task effect (non‐target minus target) were extracted from continuous electroencephalography recording. The frontal midline channel Fz was identified a priori as the main channel of interest. Aβ accumulation was characterized with [18F] Florbetapir positron emission tomography scans. Independent t‐tests, Fisher’s Exact, or Mann‐Whitney U tests were employed to compare baseline characteristics between groups. Linear mixed models with random intercept were used to compare changes in P3 peak amplitude and latency. Group (CNAβ+ vs CNAβ‐), time (baseline, 1‐year), and n‐back (0, 1, 2) were entered as main effects. The main analysis of interest was the interaction between group and time.ResultBaseline age, sex, MOCA scores, and n‐back accuracy and response times did not differ (p&gt;0.11) between CNAβ+ and CNAβ‐ groups [Table 1]. Additionally, no longitudinal changes in MOCA scores or n‐back performance were observed between groups (p&gt;0.41). A significant group by time interaction effect in P3 peak amplitude at Fz was found between CNAβ+ and CNAβ‐ participants (p = 0.049). The P3 peak amplitude increased by 48% in CNAβ+ participants, whereas only a 19% increase was observed in CNAβ‐ participants.ConclusionThe ERP revealed significant changes over time in P3 amplitude for the CNAβ+ participants compared to the CNAβ‐ controls. The greater increase of CNAβ+ task effect amplitude likely represents a growing imbalance in task specific resource allocation. Further investigation of this phenomenon is warranted to evaluate neuronal activity of preclinical AD and the use of P3 ERP as a potential screening tool.

A 4-Year Follow-Up of Subjects with Visually Equivocal Amyloid Positron Emission Tomography Findings from the Alzheimer's Disease Neuroimaging Initiative Cohort.

To date, the clinical significance of visually equivocal amyloid positron emission tomography (PET) has not been well established. We studied the clinical significance of equivocal amyloid PET images from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Subjects with F-18 florbetapir PET scans at baseline who were followed up for 4 years were selected. Clinical characteristics, imaging biomarkers, cognitive function, and rate of conversion to AD were compared in subjects with visually equivocal findings. Of 249 subjects who completed the follow-up, 153 (61.4%), 20 (8.0%), and 129 (30.5%) were F-18 florbetapir-negative, -equivocal, and -positive, respectively. The mean standardized uptake value ratios (SUVR) of F-18 florbetapir PET were 0.75 ± 0.04, 0.85 ± 0.10, and 1.00 ± 0.09 for each group (p <0.001 between groups), and 15.0%, 70.0%, and 98.7% of patients were quantitatively above the positive threshold. The change in the SUVR of F-18 florbetapir PET was higher in the equivocal (6.09 ± 3.61%, p <0.001) and positive (3.13 ± 4.38%, p <0.001) groups than the negative group (0.88 ± 4.28%). Among the subjects with normal or subjective memory impairment and mild cognitive impairment, 5.3% with negative amyloid PET and 37.5% with positive amyloid PET converted to AD over the 4-year period. None of the equivocal amyloid PET subjects converted to AD during this period. Approximately 8% of subjects from the ADNI cohort showed visually equivocal amyloid PET scans with intermediate load and rapid accumulation of amyloid, but did not convert to AD during the 4-year follow-up.

Association of quality of life with structural, functional and molecular brain imaging in community-dwelling older adults

BackgroundAs the population ages, maintaining mental health and well-being of older adults is a public health priority. Beyond objective measures of health, self-perceived quality of life (QoL) is a good indicator of successful aging. In older adults, it has been shown that QoL is related to structural brain changes. However, QoL is a multi-faceted concept and little is known about the specific relationship of each QoL domain to brain structure, nor about the links with other aspects of brain integrity, including white matter microstructure, brain perfusion and amyloid deposition, which are particularly relevant in aging. Therefore, we aimed to better characterize the brain biomarkers associated with each QoL domain using a comprehensive multimodal neuroimaging approach in older adults. MethodsOne hundred and thirty-five cognitively unimpaired older adults (mean age ± SD: 69.4 ± 3.8 y) underwent structural and diffusion magnetic resonance imaging, together with early and late florbetapir positron emission tomography scans. QoL was assessed using the brief version of the World Health Organization's QoL instrument, which allows measuring four distinct domains of QoL: self-perceived physical health, psychological health, social relationships and environment. Multiple regression analyses were carried out to identify the independent global neuroimaging predictor(s) of each QoL domain, and voxel-wise analyses were then conducted with the significant predictor(s) to highlight the brain regions involved. Age, sex, education and the other QoL domains were entered as covariates in these analyses. Finally, forward stepwise multiple regressions were conducted to determine the specific items of the relevant QoL domain(s) that contributed the most to these brain associations. ResultsOnly physical health QoL was associated with global neuroimaging values, specifically gray matter volume and white matter mean kurtosis, with higher physical health QoL being associated with greater brain integrity. These relationships were still significant after correction for objective physical health and physical activity measures. No association was found with global brain perfusion or global amyloid deposition. Voxel-wise analyses revealed that the relationships with physical health QoL concerned the anterior insula and ventrolateral prefrontal cortex, and the corpus callosum, corona radiata, inferior frontal white matter and cingulum. Self-perceived daily living activities and self-perceived pain and discomfort were the items that contributed the most to these associations with gray matter volume and white matter mean kurtosis, respectively. ConclusionsBetter self-perceived physical health, encompassing daily living activities and pain and discomfort, was the only QoL domain related to brain structural integrity including higher global gray matter volume and global white matter microstructural integrity in cognitively unimpaired older adults. The relationships involved brain structures belonging to the salience network, the pain pathway and the empathy network. While previous studies showed a link between objective measures of physical health, our findings specifically highlight the relevance of monitoring and promoting self-perceived physical health in the older population. Longitudinal studies are needed to assess the direction and causality of the relationships between QoL and brain integrity.

Repeatability of parametric methods for [18F]florbetapir imaging in Alzheimer’s disease and healthy controls: A test–retest study

Accumulation of amyloid beta (Aβ) is one of the pathological hallmarks of Alzheimer’s disease (AD), which can be visualized using [18F]florbetapir positron emission tomography (PET). The aim of this study was to evaluate various parametric methods and to assess their test-retest (TRT) reliability. Two 90 min dynamic [18F]florbetapir PET scans, including arterial sampling, were acquired (n = 8 AD patient, n = 8 controls). The following parametric methods were used; (reference:cerebellum); Logan and spectral analysis (SA), receptor parametric mapping (RPM), simplified reference tissue model2 (SRTM2), reference Logan (rLogan) and standardized uptake value ratios (SUVr(50–70)). BPND+1, DVR, VT and SUVr were compared with corresponding estimates (VT or DVR) from the plasma input reversible two tissue compartmental (2T4k_VB) model with corresponding TRT values for 90-scan duration. RPM (r2 = 0.92; slope = 0.91), Logan (r2 = 0.95; slope = 0.84) and rLogan (r2 = 0.94; slope = 0.88), and SRTM2 (r2 = 0.91; slope = 0.83), SA (r2 = 0.91; slope = 0.88), SUVr (r2 = 0.84; slope = 1.16) correlated well with their 2T4k_VB counterparts. RPM (controls: 1%, AD: 3%), rLogan (controls: 1%, AD: 3%) and SUVr(50–70) (controls: 3%, AD: 8%) showed an excellent TRT reliability. In conclusion, most parametric methods showed excellent performance for [18F]florbetapir, but RPM and rLogan seem the methods of choice, combining the highest accuracy and best TRT reliability.

Evaluation of [18F]-N-Methyl lansoprazole as a Tau PET Imaging Agent in First-in-Human Studies

Development of positron emission tomography (PET) imaging agents capable of quantifying tau aggregates in neurodegenerative disorders such as Alzheimer's disease (AD) is of enormous importance in the field of dementia research. The aim of the present study was to conduct first-in-man imaging studies with the potential novel tau imaging agent [18F]N-methyl lansoprazole ([18F]NML). Herein we report validation of the synthesis of [18F]NML for clinical use by labeling the trifluoromethyl group via radiofluorination of the corresponding gem-difluoro enol ether precursor. This is the first use of this method for clinical production of PET radiotracers and confirmed that it can be readily implemented at multiple production facilities to provide [18F]NML in good noncorrected radiochemical yield (3.4 ± 1.5 GBq, 4.6% ± 2.6%) and molar activity (120.1 ± 186.3 GBq/μmol), excellent radiochemical purity (>97%), and suitable for human use (n = 15). With [18F]NML in hand, we conducted rodent biodistribution, estimates of human dosimetry, and preliminary evaluation of [18F]NML in human subjects at two imaging sites. Healthy controls (n = 4) and mildly cognitively impaired (MCI) AD patients (n = 6) received [18F]NML (tau), [18F]AV1451 (tau), and [18F]florbetaben or [18F]florbetapir (amyloid) PET scans. A single progressive supranuclear palsy (PSP) patient also received [18F]NML and [18F]AV1451 PET scans. [18F]NML showed good brain uptake, reasonable pharmacokinetics, and appropriate imaging characteristics in healthy controls. The mean ± SD of the administered mass of [18F/19F]NML was 2.01 ± 2.17 μg (range, 0.16-8.27 μg) and the mean administered activity was 350 ± 62 MBq (range, 199-403 MBq). There were no adverse or clinically detectable pharmacologic effects in any of the 11 subjects, and no significant changes in vital signs were observed. However, despite high affinity for tau in vitro, brain retention in MCI/AD and PSP patients was low, and there was no evidence of specific signals in vivo that corresponded to tau. Although it is still unclear why clinical translation of the radiotracer was unsuccessful, we nevertheless conclude that further development of [18F]NML as a tau PET imaging agent is not warranted at this time.

HEARING IMPAIRMENT, COGNITIVE PERFORMANCE, AND BETA-AMYLOID DEPOSITION IN THE ARIC-PET AMYLOID IMAGING STUDY

Hearing impairment is a risk factor for dementia but the mechanism underlying this association is unknown. We investigated the relationship between hearing and cognitive performance and brain β-amyloid deposition in 252 adults aged 67-88 years (37% black race) without dementia from three U.S. communities. Global cortical standardized uptake value ratios (SUVRs) were calculated from florbetapir-positron emission tomography scans, with elevated SUVR defined as >1.2 (the median value). Air conduction hearing threshold levels for the frequencies of 0.5, 1, 2 and 4 kHz were obtained by pure tone audiometry and averaged for the better-hearing ear to yield a pure tone average (PTA) in decibels hearing level (dB). A composite cognitive score was created from ten neuropsychological tests summarized using latent variable methods. Multivariable-adjusted linear and Poisson regression with robust standard errors were used to estimate the average difference in cognitive scores and prevalence of elevated SUVR, respectively, by hearing impairment status. In analyses adjusted for age, sex, education and APOE ε4 status, hearing was not associated with elevated SUVR [prevalence ratio per 10 db increase (worse hearing) = 0.94 (95% CI: 0.84, 1.04)]. Results did not differ by race. In contrast, each 10 db increase in hearing impairment was associated with 0.08 standard deviation (95% CI: 0.02, 0.15) lower cognitive score, after adjustment for demographic and cardiovascular factors. Poorer hearing is associated with poorer cognitive performance but not with amyloid deposition, suggesting that the mechanism underlying the relationship between hearing and cognition may be independent of Alzheimer’s-related pathologic brain changes.

APOE Effect on Amyloid-β PET Spatial Distribution, Deposition Rate, and Cut-Points.

There are conflicting results regarding how APOE genotype, the strongest genetic risk factor for Alzheimer's disease (AD), influences spatial and longitudinal amyloid-β (Aβ) deposition and its impact on the selection of biomarker cut-points. In our study, we sought to determine the impact of APOE genotype on cross-sectional and longitudinal florbetapir positron emission tomography (PET) amyloid measures and its impact in classification of patients and interpretation of clinical cohort results. We included 1,019 and 1,072 Alzheimer's Disease Neuroimaging Initiative participants with cerebrospinal fluid Aβ1-42 and florbetapir PET values, respectively. 623 of these subjects had a second florbetapir PET scans two years after the baseline visit. We evaluated the effect of APOE genotype on Aβ distribution pattern, pathological biomarker cut-points, cross-sectional clinical associations with Aβ load, and longitudinal Aβ deposition rate measured using florbetapir PET scans. 1) APOEɛ4 genotype influences brain amyloid deposition pattern; 2) APOEɛ4 genotype does not modify Aβ biomarker cut-points estimated using unsupervised mixture modeling methods if white matter and brainstem references are used (but not when cerebellum is used as a reference); 3) findings of large differences in Aβ biomarker value differences based on APOE genotype are due to increased probability of having AD neuropathology and are most significant in mild cognitive impairment subjects; and 4) APOE genotype and age (but not gender) were associated with increased Aβ deposition rate. APOEɛ4 carrier status affects rate and location of brain Aβ deposition but does not affect choice of biomarker cut-points if adequate references are selected for florbetapir PET processing.

Blunted cerebrovascular response is associated with elevated beta-amyloid

The goal of this study was to explore the association of beta-amyloid accumulation and cerebrovascular response (CVR) in cognitively normal older adults. Beta-amyloid accumulation was characterized with [18F] Florbetapir positron emission tomography scans. CVR was calculated as middle cerebral artery blood flow velocity change from rest to moderate intensity exercise. We found that individuals with elevated beta-amyloid aggregation had a blunted CVR (n = 25, age 70.1 ± 4.8; 3.3 ± 3.7 cm/s) compared to non-elevated individuals (n = 45, age 72.0 ± 4.9; 7.2 ± 5.0 cm/s, p < 0.001). Further, greater beta-amyloid burden was linearly associated with less CVR across all participants (b = −11.7, p < 0.001). Greater CVR and less beta-amyloid burden were associated with processing speed (p < 0.05). This study is the first to show that CVR from rest to exercise is blunted across increased global beta-amyloid burden.

Association Between Midlife Vascular Risk Factors and Estimated Brain Amyloid Deposition

Midlife vascular risk factors have been associated with late-life dementia. Whether these risk factors directly contribute to brain amyloid deposition is less well understood. To determine if midlife vascular risk factors are associated with late-life brain amyloid deposition, measured using florbetapir positron emission tomography (PET). The Atherosclerosis Risk in Communities (ARIC)-PET Amyloid Imaging Study, a prospective cohort study among 346 participants without dementia in 3 US communities (Washington County, Maryland; Forsyth County, North Carolina; and Jackson, Mississippi) who have been evaluated for vascular risk factors and markers since 1987-1989 with florbetapir PET scans in 2011-2013. Positron emission tomography image analysis was completed in 2015. Vascular risk factors at ARIC baseline (age 45-64 years; risk factors included body mass index ≥30, current smoking, hypertension, diabetes, and total cholesterol ≥200 mg/dL) were evaluated in multivariable models including age, sex, race, APOE genotype, and educational level. Standardized uptake value ratios (SUVRs) were calculated from PET scans and a mean global cortical SUVR was calculated. Elevated florbetapir (defined as a SUVR >1.2) was the dependent variable. Among 322 participants without dementia and with nonmissing midlife vascular risk factors at baseline (mean age, 52 years; 58% female; 43% black), the SUVR (elevated in 164 [50.9%] participants) was measured more than 20 years later (median follow-up, 23.5 years; interquartile range, 23.0-24.3 years) when participants were between 67 and 88 (mean, 76) years old. Elevated body mass index in midlife was associated with elevated SUVR (odds ratio [OR], 2.06; 95% CI, 1.16-3.65). At baseline, 65 participants had no vascular risk factors, 123 had 1, and 134 had 2 or more; a higher number of midlife risk factors was associated with elevated amyloid SUVR at follow-up (30.8% [n = 20], 50.4% [n = 62], and 61.2% [n = 82], respectively). In adjusted models, compared with 0 midlife vascular risk factors, the OR for elevated SUVR associated with 1 vascular risk factor was 1.88 (95% CI, 0.95-3.72) and for 2 or more vascular risk factors was 2.88 (95% CI, 1.46-5.69). No significant race × risk factor interactions were found. Late-life vascular risk factors were not associated with late-life brain amyloid deposition (for ≥2 late-life vascular risk factors vs 0: OR, 1.66; 95% CI, 0.75-3.69). An increasing number of midlife vascular risk factors was significantly associated with elevated amyloid SUVR; this association was not significant for late-life risk factors. These findings are consistent with a role of vascular disease in the development of Alzheimer disease.

Use of white matter reference regions for detection of change in florbetapir positron emission tomography from completed phase 3 solanezumab trials

IntroductionWe compared subject-specific white matter (SSWM) and whole cerebellum (CBL) reference regions for power to detect longitudinal change in amyloid positron emission tomography signal. MethodsPositive florbetapir positron emission tomography scans were analyzed from participants (66 placebo treated and 63 solanezumab treated) with mild dementia caused by Alzheimer's disease from the EXPEDITION and EXPEDITION2 studies. For comparison to CBL, a second normalization was performed on longitudinal data using an SSWM correction factor (SSWM normalization ratio [SSWMnr]). Analysis of covariance assessed baseline to 18-month change between treatment with solanezumab and placebo. Sample and effect size estimations provided magnitude of observed treatment changes. ResultsLongitudinal percent change between placebo and solanezumab using CBL was not significant (P = .536) but was significant for SSWMnr (P = .042). Compared with CBL, SSWMnr technique increased the power to detect a treatment difference, more than tripling the effect size and reducing the sample size requirements by 85% to 90%. DiscussionAdjusting longitudinal standardized uptake value ratios with an SSWM reference region in these antiamyloid treatment trials increased mean change detection and decreased variance resulting in the substantial improvement in statistical power to detect change.

β-Amyloid is associated with aberrant metabolic connectivity in subjects with mild cognitive impairment.

Positron emission tomography (PET) studies using [18F]2-fluoro-2-deoxyglucose (FDG) have identified a well-defined pattern of glucose hypometabolism in Alzheimer's disease (AD). The assessment of the metabolic relationship among brain regions has the potential to provide unique information regarding the disease process. Previous studies of metabolic correlation patterns have demonstrated alterations in AD subjects relative to age-matched, healthy control subjects. The objective of this study was to examine the associations between β-amyloid, apolipoprotein E ɛ4 (APOE ɛ4) genotype, and metabolic correlations patterns in subjects diagnosed with mild cognitive impairment (MCI). Mild cognitive impairment subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study were categorized into β-amyloid-low and β-amyloid-high groups, based on quantitative analysis of [18F]florbetapir PET scans, and APOE ɛ4 non-carriers and carriers based on genotyping. We generated voxel-wise metabolic correlation strength maps across the entire cerebral cortex for each group, and, subsequently, performed a seed-based analysis. We found that the APOE ɛ4 genotype was closely related to regional glucose hypometabolism, while elevated, fibrillar β-amyloid burden was associated with specific derangements of the metabolic correlation patterns.

A consecutive case series experience with [18 F] florbetapir PET imaging in an urban dementia center: impact on quality of life, decision making, and disposition

BackgroundIdentification and quantification of fibrillar amyloid in brain using positron emission tomography (PET) imaging and Amyvid™ ([18 F] Amyvid, [18 F] florbetapir, 18 F-AV-45) was recently approved by the US Food and Drug Administration as a clinical tool to estimate brain amyloid burden in patients being evaluated for cognitive impairment or dementia. Imaging with [18 F] florbetapir offers in vivo confirmation of the presence of cerebral amyloidosis and may increase the accuracy of the diagnosis and likely cause of cognitive impairment (CI) or dementia. Most importantly, amyloid imaging may improve certainty of etiology in situations where the differential diagnosis cannot be resolved on the basis of standard clinical and laboratory criteria.ResultsA consecutive case series of 30 patients (age 50-89; 16 M/14 F) were clinically evaluated at a cognitive evaluation center of urban dementia center and referred for [18 F] florbetapir PET imaging as part of a comprehensive dementia workup. Evaluation included neurological examination and neuropsychological assessment by dementia experts. [18 F] florbetapir PET scans were read by trained nuclear medicine physicians using the qualitative binary approach. Scans were rated as either positive or negative for the presence of cerebral amyloidosis. In addition to a comprehensive dementia evaluation, post [18 F] florbetapir PET imaging results caused diagnoses to be changed in 10 patients and clarified in 9 patients. Four patients presenting with SCI were negative for amyloidosis. These results show that [18 F] florbetapir PET imaging added diagnostic clarification and discrimination in over half of the patients evaluated.ConclusionsAmyloid imaging provided novel and essential data that: (1) caused diagnosis to be revised; and/or (2) prevented the initiation of incorrect or suboptimal treatment; and/or (3) avoided inappropriate referral to an anti-amyloid clinical trial.

Comparison of florbetapir positron emission tomography scans with cerebrospinal fluid biomarkers in healthy individuals and people with mild cognitive impairment or Alzheimer's disease dementia

We assessed the relationships between florbetapir positron emission tomography (FBP-PET) scans and cerebrospinal fluid (CSF) biomarkers in healthy control (HC), clinically diagnosed mild cognitive impairment (MCI), and Alzheimer's disease (AD) dementia subjects. Data were obtained in August 2012 from the Alzheimer's Disease Neuroimaging Initiative (ADNI), ADNI Grand Opportunity (ADNI-GO), and ADNI-2 studies for all HC, MCI, or AD subjects whose clinical and CSF data had been collected ± 90 days of their FBP-PET scan. Variables included demographic, cognitive, CSF beta-amyloid (Aβ), and tau levels and ratios; and FBP-PET standard uptake value ratio (SUVR) values for composite and 6 regions of interest. Pearson correlation coefficients were calculated among clinical, 5 CSF, and 7 FBP-PET variables. Multinomial logit regression modeling with HC subjects as reference group assessed the association between clinical diagnosis and CSF and/or FBP-PET variables. Likelihood ratio test was used to examine whether adding CSF biomarkers to the model which regresses clinical diagnosis on FBP-PET SUVRs significantly improved model fit, and vice versa. Subjects had mean ages of 76.5 (HC, n=187), 72.6 (MCI, n=320), or 75.5 (AD, n=70) years and were mostly male (50.8%, 58.4%, 64.3%) and white (93.0%, 92.8%, 95.7%). The highest correlations (r >0.60) were observed between FBP-PET anterior and posterior cingulate and composite SUVRs with CSF Aβ, tau/Aβ ratio, and phosphorylated tau/Aβ ratio for HC and MCI subjects, but only between FBP-PET anterior cingulate and composite SUVRs with CSF Aβ for AD. In multinomial logit regression modeling, neither CSF biomarkers (p=0.096) nor FBP-PET SUVRs (p=0.675) significantly added information to explain clinical diagnostic group when in the presence of the other biomarker type. Our findings suggest much overlap among CSF biomarkers and FBP-PET SUVRs in discerning HC, MCI, and AD subjects. More of the CSF and FBP-PET variables showed strong correlations in HC and MCI subjects but fewer for AD subjects. In this ADNI cohort, FBP-PET and CSF seem similarly suited to distinguish between the tested participant groups, with no statistically significant gain in information achieved by combining the measures.

Vertexwise discriminant analysis of ADNI [18F]florbetapir PET images for classification of amyloid-positive and amyloid-negative subjects

Classification of subjects as Amyloid-Positive (Aβ+) or Amyloid-Negative (Aβ-) based on Amyloid positron emission tomography (PET) scans is increasingly utilized in research studies and clinical practice. While qualitative, visual assessment is currently the gold-standard approach, automated classification techniques possess the inherent advantages of being objective, reproducible, and efficient. The goal of this work was to develop a statistically-driven approach that will facilitate automated classification of subjects based on conventional [18F]florbetapir PET scans. [18F]florbetapir PET and 3D T1-weighted MR images were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) normal control (NC) mild cognitive impairment (MCI) subjects. The PET volumes were registered to a customized MRI template in MNI stereotaxic space, and standardized uptake value ratio (SUVR) images were generated and projected onto each subject's cortical surface using Biospective's fully-automated PIANO TM image processing software. Subjects were initially classified as Aβ+ or Aβ- based on a visual evaluation of the [18F]florbetapir PET scans. A vertexwise discriminant analysis was performed in order to generate cortical surface parametric maps of accuracy, sensitivity, and specificity. A non-parametric conjunction analysis with multiple comparisons-controlled thresholding generated a Statistical Region-of-Interest (statROI). Receiver operating characteristic (ROC) analysis, based on individual statROI measurements, was used to obtain a threshold value for the separation of Aβ+ and Aβ- subjects. The vertexwise discriminant analysis resulted in parametric maps with maximum accuracy, sensitivity, and specificity values of 0.91 0.94, 0.95, respectively. The statROI included sub-regions of the precuneus, anterior/posterior cingulate cortex, medial/lateral frontal cortex, lateral temporal lobe, and inferior parietal lobule. ROCs based on this composite statROI yielded an optimal threshold for classification of Aβ+ and Aβ- subjects. This novel, vertexwise discrimant analysis approach allowed for determination of an objective statROI and associated threshold that effectively discriminated Aβ+ or Aβ- subjects. We anticipate that the statROI defined in this study will replace existing “composite ROIs”, and allow for standardized analysis across studies. Ultimately, automated classification of subjects based on Amyloid PET scans may complement or supplant visual reads in routine clinical practice and for eligibility assessment in clinical trials.

Impact of 18F-florbetapir PET imaging of β-amyloid neuritic plaque density on clinical decision-making

18F-florbetapir positron emission tomography (PET) imaging of the brain is now approved by the Food and Drug Administration (FDA) approved for estimation of β-amyloid neuritic plaque density when evaluating patients with cognitive impairment. However, its impact on clinical decision-making is not known. We present 11 cases (age range 67–84) of cognitively impaired subjects in whom clinician surveys were done before and after PET scanning to document the theoretical impact of amyloid imaging on the diagnosis and treatment plan of cognitively impaired subjects. Subjects have been clinically followed for about 5 months after the PET scan. Negative scans occurred in five cases, leading to a change in diagnosis for four patients and a change in treatment plan for two of these cases. Positive scans occurred in six cases, leading to a change in diagnosis for four patients and a change in treatment plan for three of these cases. Following the scan, only one case had indeterminate diagnosis. Our series suggests that both positive and negative florbetapir PET scans may enhance diagnostic certainty and impact clinical decision-making. Controlled longitudinal studies are needed to confirm our data and determine best practices.