Neuropathologic Heterogeneity Does Not Impair Florbetapir-Positron Emission Tomography Postmortem Correlates

Dugger, Brittany N.; Clark, Christopher M.; Serrano, Geidy E.; Mariner, Monica; Bedell, Barry J.; Coleman, Robert E.; Doraiswamy, P. Murali; Lu, Ming; Fleisher, Adam; Reiman, Eric M.; Sabbagh, Marwan N.; Sadowsky, Carl; Schneider, Julie A.; Zehntner, Simone P.; Carpenter, Alan; Joshi, Abhinay D.; Mintun, Mark A.; Pontecorvo, Michael J.; Skovronsky, Daniel; Sue, Lucia I.; Beach, Thomas G.

doi:10.1097/nen.0000000000000028

Cited by 37 publications

(37 citation statements)

References 31 publications

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“…Less commonly, researchers compute a cerebral-to-reference region distribution volume ratio or other quantitative measures using longer, dynamically acquired PET scans and the same cerebral and reference ROIs. With conventional reference ROIs, several radioligands have demonstrated a close association between cross-sectional PET SUVR or distribution volume ratio measurements and subsequent postmortem histopathologic measurements of fibrillar Ab burden and have been used to define relevant thresholds for distinguishing between individuals with and individuals without moderate to severe neuritic plaques (2,8,16,17).…”

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confidence: 99%

Improved Power for Characterizing Longitudinal Amyloid-β PET Changes and Evaluating Amyloid-Modifying Treatments with a Cerebral White Matter Reference Region

et al. 2015

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In this article, we describe an image analysis strategy with improved power for tracking longitudinal amyloid-β (Aβ) PET changes and evaluating Aβ-modifying treatments. Methods: Our aims were to compare the power of template-based cerebellar, pontine, and cerebral white matter reference regions to track 24-mo florbetapir standardized uptake value (SUV) ratio (SUVR) changes; to relate those changes to 24-mo clinical declines; and to evaluate Aβ-modifying treatments in Aβ-positive (Aβ1) and Aβ-negative (Aβ−) patients with probable Alzheimer dementia (pAD), in patients with mild cognitive impairment (MCI), in cognitively normal controls (NCs), and in cognitively normal apolipoprotein E4 (APOE4) carriers and noncarriers. We used baseline and follow-up (∼24 mo) florbetapir PET scans from 332 Aβ1 and Aβ− subjects participating in the multicenter Alzheimer's Disease Neuroimaging Initiative. Each of the proposed analyses included 31 pAD patients, 187 MCI patients, and 114 NCs. Cerebral-to-white matter, cerebellar, and pontine SUVRs were characterized in terms of their longitudinal variability; their power to track longitudinal fibrillar Aβ increases in Aβ1 and Aβ− subgroups and cognitively normal APOE4 carriers and noncarriers; the sample sizes needed to detect attenuated accumulation of or clearance of fibrillar Aβ accumulation in randomized clinical trials; and their ability to relate 24-mo fibrillar Aβ increases to clinical declines. Results: As predicted, cerebral-to-white matter SUVR changes were significantly less variable and had significantly greater power to detect 24-mo fibrillar Aβ increases and evaluate Aβ-modifying treatment effects in Aβ1 pAD, MCI, and NC subjects and cognitively normal APOE4 carriers. They were also distinguished by the ability to detect significant associations between 24-mo Aβ increases and clinical declines. Conclusion: A cerebral white matter reference region may improve the power to track longitudinal fibrillar Aβ increases, to characterize their relationship to longitudinal clinical declines, and to evaluate Aβ-modifying treatments in randomized clinical trials. PET ligands (1-15) have made it possible to investigate the fibrillar amyloid-b (Ab) burden in living people; to clarify its relationship to the dementia, mild cognitive impairment (MCI), and preclinical stages of Alzheimer disease (AD); to characterize the extent to which cross-sectional measurements predict subsequent clinical declines; to track longitudinal changes; and to help evaluate Ab-modifying treatments.Researchers commonly compute a semiquantitative cerebral-toreference region standardized uptake value ratio (SUVR) using PET counts from a cerebral region of interest (ROI) and from a whole cerebellar (2,3), cerebellar gray matter (10), or pontine (8) reference ROI that is thought to be relatively devoid of fibrillar Ab. Less commonly, researchers compute a cerebral-to-reference region distribution volume ratio or other quantitative measures using longer, dynamically acquired PET scans and the same cerebral and refe...

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confidence: 99%

Improved Power for Characterizing Longitudinal Amyloid-β PET Changes and Evaluating Amyloid-Modifying Treatments with a Cerebral White Matter Reference Region

et al. 2015

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“…The SUVR involves calculating the radioactivity of a specific region compared with another reference range. An interesting side note of this study was that patients with AD and Lewy bodies had significantly lower SUVRs compared with patients with AD without Lewy bodies [26]. This study demonstrates the ability of florbetapir PET scans to discriminate the presence of amyloid, despite the high clinical/pathologic variability of AD.…”

Section: [ 18 F] Av-45 or Florbetapirmentioning

confidence: 57%

Amyloid Imaging: Poised for Integration into Medical Practice

Anand

Sabbagh

2017

Neurotherapeutics

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Amyloid imaging represents a significant advance as an adjunct in the diagnosis of Alzheimer's disease (AD) because it is the first imaging modality that identifies in vivo changes known to be associated with the pathogenesis. Initially, 11 C-PIB was developed, which was the prototype for many 18 F compounds, including florbetapir, florbetaben, and flutemetamol, among others. Despite the high sensitivity and specificity of amyloid imaging, it is not commonly used in clinical practice, mainly because it is not reimbursed under current Center for Medicare and Medicaid Services guidelines in the USA. To guide the field in who would be most appropriate for the utility of amyloid positron emission tomography, current studies are underway [Imaging Dementia Evidence for Amyloid Scanning (IDEAS) Study] that will inform the field on the utilization of amyloid positron emission tomography in clinical practice. With the advent of monoclonal antibodies that specifically target amyloid antibody, there is an interest, possibly a mandate, to screen potential treatment recipients to ensure that they are suitable for treatment. In this review, we summarize progress in the field to date.

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“…When diagnosing AD, using the most commonly used combination of the clinical and neuropathological definitions of AD, sensitivity and specificity are both only approximately 70% (3). Of the many clinical biomarkers in development, only amyloid PET imaging has been approved by the US FDA, but amyloid imaging cannot assess the distribution of p-tau or neurofibrillary tangles, fully define the pathological stage of AD or identify diverse types of pathological heterogeneity (9, 10), which could cause differential subject responses in clinical trials of new potential therapies. Furthermore, while a negative amyloid PET scan would effectively exclude AD as a cause of dementia, there are no clinical methods available to identify the molecular basis of any of the non-AD dementias.…”

Section: Discussionmentioning

confidence: 99%

“…The antibodies used for p-synuclein (raised against alpha-synuclein phosphorylated at serine 129) and p-TDP-43 (TDP-43 phosphorylated at serine 409/410) were privately developed and their characterization has been previously described (30–36). The signal development steps have been described in previous publications (10). These were identical in the procedures used for p-tau, Aβ, and pTDP-43 except for differing epitope exposure methods: 20 minutes in 80% formic acid for p-tau and Aβ; 20 minutes in boiling 0.1 M sodium citrate for p-TDP-43; and 20 minutes proteinase K pretreatment for p-synuclein.…”

Section: Methodsmentioning

confidence: 99%

Feasibility Study: Comparison of Frontal Cortex Needle Core Versus Open Biopsy for Detection of Characteristic Proteinopathies of Neurodegenerative Diseases

Serrano

Intorcia

Carew

et al. 2015

J Neuropathol Exp Neurol

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The clinical diagnosis and classification of neurodegenerative diseases based on clinical examination or available biomarkers are currently insufficiently accurate. Although histological examination is considered the gold standard for diagnosis, brain biopsies have been avoided because of the high risk-benefit ratio. However, brain biopsies have previously been performed with a craniotomy and excision of approximately 1 cc of cerebral cortex tissue, and it is possible that needle core brain biopsies would have a lower morbidity and mortality risk. Here, we compared the ability of simulated needle core biopsy versus simulated open biopsy to detect the frontal cortex histopathology associated with common neurodegenerative diseases in the elderly using 144 autopsy-proven cases. Simulated needle core biopsy, as compared to simulated open biopsy, gave close to 90% sensitivity and specificity for identifying graded densities of β-amyloid and neuritic plaques, neurofibrillary tangles, phosphorylated α-synuclein, and phosphorylated TDP-43 pathology. This study shows that the presence and densities of the most common molecular pathologies may be histopathologically assessed in simulated frontal cortex needle biopsies with accuracy very close to that obtained by open cortical biopsy. An accurate estimation of the morbidity and mortality risk associated with cortical needle core biopsy will require specifically designed clinical trials in appropriate subjects.

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Neuropathologic Heterogeneity Does Not Impair Florbetapir-Positron Emission Tomography Postmortem Correlates

Cited by 37 publications

References 31 publications

Improved Power for Characterizing Longitudinal Amyloid-β PET Changes and Evaluating Amyloid-Modifying Treatments with a Cerebral White Matter Reference Region

Improved Power for Characterizing Longitudinal Amyloid-β PET Changes and Evaluating Amyloid-Modifying Treatments with a Cerebral White Matter Reference Region

Amyloid Imaging: Poised for Integration into Medical Practice

Feasibility Study: Comparison of Frontal Cortex Needle Core Versus Open Biopsy for Detection of Characteristic Proteinopathies of Neurodegenerative Diseases

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