Spatiotemporal Distribution of β-Amyloid in Alzheimer Disease Is the Result of Heterogeneous Regional Carrying Capacities

Whittington, Alex; Sharp, David J.; Gunn, Roger N.

doi:10.2967/jnumed.117.194720

Cited by 53 publications

(56 citation statements)

References 43 publications

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“…The sequence of events of A deposition in typical late onset disease is remarkable for a tight correlation between A load across all the cortical association areas and striatum. This was recognized very early in the evaluation of A tracers (Price et al, 2005 ) and has been emphasized in more recent work (Whittington et al, 2018). Analytic approaches used by Whittington et al support the conclusion that "Aβ accumulation starts in all brain regions simultaneously and that its spatiotemporal distribution is due to heterogeneous regional carrying capacities (regional maximum possible concentration of Aβ) for the aggregated protein rather than to longer-term spreading from seed regions."…”

Section: Topology Of A Pet Tracer Retentionmentioning

confidence: 95%

Fluid and PET biomarkers for amyloid pathology in Alzheimer's disease

Cohen

Landau

Snitz

et al. 2019

Molecular and Cellular Neuroscience

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Alzheimer's disease (AD) is characterized by amyloid plaques and tau pathology (neurofibrillary tangles and neuropil threads). Amyloid plaques are primarily composed of aggregated and oligomeric β-amyloid (Aβ) peptides ending at position 42 (Aβ42). The development of fluid and PET biomarkers for Alzheimer's disease (AD), has allowed for detection of A pathology in vivo and marks a major advancement in understanding the role of A in Alzheimer's disease (AD). In the recent National Institute on Aging and Alzheimer's Association (NIA-AA) Research Framework, AD is defined by the underlying pathology as measured in patients during life by biomarkers (Jack et al., 2018), while clinical symptoms are used for staging of the disease. Therefore, sensitive, specific and robust biomarkers to identify brain amyloidosis are central in AD research. Here, we discuss fluid and PET biomarkers for Aβ and their application. Alzheimer's disease (AD) is characterized by amyloid plaques and tau pathology (neurofibrillary tangles and neuropil threads), together with neuronal and synaptic degeneration, in cortical areas of the brain (Scheltens et al., 2016). Amyloid plaques are primarily composed of aggregated and oligomeric β-amyloid (Aβ) peptides ending at position 42 (Aβ42). In the recent National Institute on Aging and Alzheimer's Association (NIA-AA) Research Framework, AD is defined by the underlying pathology as measured in patients during life by biomarkers (Jack et al., 2018), while clinical symptoms (or absence thereof) is used for staging of the disease. Following these criteria, brain amyloidosis is a key factor in AD, since it is the earliest change found in the Alzheimer's continuum, and the presence of biomarker signs of amyloidosis, with normal cognition and often, normal tau and neurodegeneration biomarkers, allows for a diagnosis of preclinical Alzheimer's pathologic change (or preclinical AD). Therefore, sensitive, specific and robust methods to identify brain amyloidosis are central in AD research, drug development and clinical management. In addition to early diagnosis, amyloid biomarkers can be used to monitor treatment effects of drugs targeting Aβ, and are essential in clinical and epidemiological studies exploring AD pathophysiology and factors related to both genetic and environmental risk. AD research and development currently benefit from the availability of both fluid and positron emission tomography (PET) biomarkers to assess brain amyloidosis. Fluid and PET biomarkers provide overlapping, but partially independent, information that can be used to test hypotheses and make inferences about the neurophysiology underlying the initiation of amyloid deposition and disease progression. Fluid biomarkers for Aβ pathology The best-established fluid biomarkers for cerebral Aβ pathology are the 42 amino acid form of Aβ (Aβ42) and the Aβ42/40 ratio when measured in cerebrospinal fluid (CSF) (Ashton et al., 2018). Numerous studies have consistently shown a decrease in CSF Aβ42 in the dementia stage of AD, with meta-ana...

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Section: Topology Of A Pet Tracer Retentionmentioning

confidence: 95%

Fluid and PET biomarkers for amyloid pathology in Alzheimer's disease

Cohen

Landau

Snitz

et al. 2019

Molecular and Cellular Neuroscience

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“…On the basis of our prior spatiotemporal modeling work (14), we hypothesized that an 18 F-florbetapir SUVr (gray matter cerebellum reference) image, spatially normalized into MNI152 space, could be effectively modeled using a linear combination of previously derived canonic images for the nonspecific binding NS and carrying capacity K (19). Therefore,…”

Section: Definition Of Aβ Lmentioning

confidence: 99%

Amyloid Load: A More Sensitive Biomarker for Amyloid Imaging

Whittington

Gunn

2018

J Nucl Med

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Amyloid-β (Aβ) plays a key role in the pathogenesis of Alzheimer disease (AD) and can be imaged in vivo using 18 F-florbetapir PET. A composite SUV ratio (SUVr) is a commonly used outcome measure for quantifying the global Aβ burden; however, sensitivity is suboptimal and can lead to low power in clinical trials. We introduce amyloid load, Aβ L , as a novel biomarker to quantify the global Aβ burden along with an automated algorithm for its calculation (Amyloid IQ). Aβ L is evaluated on cross-sectional and longitudinal data obtained from the Alzheimer's Disease Neuroimaging Initiative. The cross-sectional data consisted of 769 subjects across the disease spectrum (211 healthy controls, 223 patients with early mild cognitive impairment, 204 with late mild cognitive impairment, and 132 with AD). The distributions of Aβ L in the 4 different classifications were compared, and the same analyses were applied to a composite SUVr outcome measure. The effect sizes (Hedges g) between all but one classification were higher for Aβ L than for composite SUVr, with the mean difference being 46%. Of the patients with early mild cognitive impairment, 147 had a 2-y follow-up scan, and the effect size between baseline and follow-up for Aβ L was 0.49, compared with 0.36 for a composite SUVr, demonstrating an equivalent increase in power for longitudinal data. These results offer evidence that Aβ L will be a valuable outcome measure in future Aβ imaging studies, providing a substantial increase in power over currently used SUVr methods.

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“…Previous studies have used several different approaches and cohorts to model amyloid trajectories with respect to age and amyloid biomarker levels 1, 14,16,36,37 . These studies suggest that individuals in the AD continuum begin accumulating beta-amyloid at different ages, but experience similar rates of amyloid accumulation for a given level of amyloidosis.…”

Section: Beta-amyloid Modeling and Rates Of Accumulationmentioning

confidence: 99%

“…Understanding the chronology of AD biomarkers and their prognostic value is important for contextualizing studies relating AD biomarkers to symptomology and other disease outcomes, and for clinical trial design. Previous studies have proposed different methods for obtaining metrics reflective of disease state 1, 3,16,[36][37][38] . In contrast to those methods, the approach in this study uses fewer model parameters and less complex model functions.…”

Section: Chronology Of Beta-amyloid Relative To Tau and Cognitive Decmentioning

confidence: 99%

“…The theoretical sigmoidal model of betaamyloid accumulation 1 suggests that individuals have relatively slow accumulation initially, followed by faster accumulation as the disease progresses. Several approaches have examined ways to empirically assess the trajectory of beta-amyloid biomarkers in AD 6,13,16,17 . These approaches often attempt to align persons within a disease state to mitigate the biomarker heterogeneity with respect to age.…”

Section: Introductionmentioning

confidence: 99%

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Amyloid duration is associated with preclinical cognitive decline and tau PET

Koscik¹,

Betthauser²,

Jonaitis³

et al. 2019

Preprint

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INTRODUCTION:This study applies a novel algorithm to longitudinal amyloid positron emission tomography (PET) imaging to identify age-heterogeneous amyloid trajectory groups, estimate the age and duration (chronicity) of amyloid positivity, and investigate chronicity in relation to cognitive decline and tau burden. METHODS:Cognitively unimpaired participants (n=257) underwent 1-4 amyloid PET scans. Group-based trajectory modeling was applied to participants with longitudinal scans (n=171) to identify and model amyloid trajectory groups, which were combined with Bayes' theorem to estimate age and chronicity of amyloid positivity. Relationships between chronicity, cognition, clinical progression and tau PET (MK-6240) were investigated using regression models. RESULTS:Chronicity explained more heterogeneity in amyloid binding than age and binary amyloid status. Chronicity was associated with faster cognitive decline, increased risk of abnormal cognition, and higher entorhinal tau. DISCUSSION: Amyloid chronicity provides unique information about cognitive decline and neurofibrillary tangle development and may be useful to investigate preclinical AD. ABBREVIATIONS AD = Alzheimer's disease PET = positron emission tomography A+/-= amyloid positive/negative GBTM = group-based trajectory modeling WRAP = Wisconsin Registry for Alzheimer's Prevention PIB = Pittsburgh Compound B PIB(+/-) = Pittsburgh Compound B positive/negative PACC-3 = three-test preclinical Alzheimer cognitive composite RAVLT = Rey Auditory Verbal Learning MR = magnetic resonance DVR = distribution volume ratio BIC = Bayesian Information Criteria WRAT3 = Wide Range Achievement Test 3 AICc = Akaike Information Criteria sd = standard deviation APOE4 = apolipoprotein ε4 LME = linear mixed effects

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Spatiotemporal Distribution of β-Amyloid in Alzheimer Disease Is the Result of Heterogeneous Regional Carrying Capacities

Cited by 53 publications

References 43 publications

Fluid and PET biomarkers for amyloid pathology in Alzheimer's disease

Fluid and PET biomarkers for amyloid pathology in Alzheimer's disease

Amyloid Load: A More Sensitive Biomarker for Amyloid Imaging

Amyloid duration is associated with preclinical cognitive decline and tau PET

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