Abstract Although amyloid imaging with PiB-PET (C-11Pittsburgh Compound-B positron emission tomography), and now with F-18-labeled tracers, has produced remarkably consistent qualitative findings ...across a large number of centers, there has been considerable variability in the exact numbers reported as quantitative outcome measures of tracer retention. In some cases this is as trivial as the choice of units, in some cases it is scanner dependent, and of course, different tracers yield different numbers. Our working group was formed to standardize quantitative amyloid imaging measures by scaling the outcome of each particular analysis method or tracer to a 0 to 100 scale, anchored by young controls (≤45 years) and typical Alzheimer's disease patients. The units of this scale have been named “Centiloids.” Basically, we describe a “standard” method of analyzing PiB PET data and then a method for scaling any “nonstandard” method of PiB PET analysis (or any other tracer) to the Centiloid scale.
Subjective cognitive complaints in otherwise normal aging are common but may be associated with preclinical Alzheimer disease in some individuals. Little is known about who is mostly likely to show ...associations between cognitive complaints and preclinical Alzheimer pathology. We sought to demonstrate associations between subjective complaints and brain amyloid-β in cognitively normal older adults; and to explore personality factors as potential moderators of this association.
Cross-sectional observational study.
Clinical neuroimaging research center.
Community volunteer sample of 92 healthy older adults, screened for normal cognition with comprehensive neuropsychological evaluation.
Subjective cognitive self-report measures included the Memory Functioning Questionnaire (MFQ), Cognitive Failures Questionnaire, and the Subjective Cognitive Complaint Scale. Personality was measured with the NEO Five Factor Inventory. Brain amyloid-β deposition was assessed with Pittsburgh compound B (PiB)-PET imaging.
One of three cognitive complaint measures, the MFQ, was associated with global PiB retention (standardized beta = -0.230, p = 0.046, adjusting for age, sex and depressive symptoms). Neuroticism moderated this association such that only high neuroticism individuals showed the predicted pattern of high complaint-high amyloid-β association.
Evidence for association between subjective cognition and brain amyloid-β deposition in healthy older adults is demonstrable but measure-specific. Neuroticism may moderate the MFQ-amyloid-β association such that it is observed in the context of higher trait neuroticism. Subjective cognitive complaints and neuroticism may reflect a common susceptibility toward psychological distress and negative affect, which are in turn risk factors for cognitive decline in aging and incident Alzheimer disease.
Background
Subject motion in positron emission tomography (PET) studies leads to image blurring and artifacts; simultaneously acquired magnetic resonance imaging (MRI) data provides a means for ...motion correction (MC) in integrated PET/MRI scanners.
Purpose
To assess the effect of realistic head motion and MR‐based MC on static 18F‐fluorodeoxyglucose (FDG) PET images in dementia patients.
Study Type
Observational study.
Population
Thirty dementia subjects were recruited.
Field Strength/Sequence
3T hybrid PET/MR scanner where EPI‐based and T1‐weighted sequences were acquired simultaneously with the PET data.
Assessment
Head motion parameters estimated from high temporal resolution MR volumes were used for PET MC. The MR‐based MC method was compared to PET frame‐based MC methods in which motion parameters were estimated by coregistering 5‐minute frames before and after accounting for the attenuation‐emission mismatch. The relative changes in standardized uptake value ratios (SUVRs) between the PET volumes processed with the various MC methods, without MC, and the PET volumes with simulated motion were compared in relevant brain regions.
Statistical Tests
The absolute value of the regional SUVR relative change was assessed with pairwise paired t‐tests testing at the P = 0.05 level, comparing the values obtained through different MR‐based MC processing methods as well as across different motion groups. The intraregion voxelwise variability of regional SUVRs obtained through different MR‐based MC processing methods was also assessed with pairwise paired t‐tests testing at the P = 0.05 level.
Results
MC had a greater impact on PET data quantification in subjects with larger amplitude motion (higher than 18% in the medial orbitofrontal cortex) and greater changes were generally observed for the MR‐based MC method compared to the frame‐based methods. Furthermore, a mean relative change of ∼4% was observed after MC even at the group level, suggesting the importance of routinely applying this correction. The intraregion voxelwise variability of regional SUVRs was also decreased using MR‐based MC. All comparisons were significant at the P = 0.05 level.
Data Conclusion
Incorporating temporally correlated MR data to account for intraframe motion has a positive impact on the FDG PET image quality and data quantification in dementia patients.
Level of Evidence: 3
Technical Efficacy: Stage 1
J. Magn. Reson. Imaging 2018;47:1288–1296.
Abstract Introduction This article reviews the work done in the Alzheimer's Disease Neuroimaging Initiative positron emission tomography (ADNI PET) core over the past 5 years, largely concerning ...techniques, methods, and results related to amyloid imaging in ADNI. Methods The PET Core has used 18 Fflorbetapir routinely on ADNI participants, with over 1600 scans available for download. Four different laboratories are involved in data analysis, and have examined factors such as longitudinal florbetapir analysis, use of 18 Ffluorodeoxyglucose (FDG)-PET in clinical trials, and relationships between different biomarkers and cognition. Results Converging evidence from the PET Core has indicated that cross-sectional and longitudinal florbetapir analyses require different reference regions. Studies have also examined the relationship between florbetapir data obtained immediately after injection, which reflects perfusion, and FDG-PET results. Finally, standardization has included the translation of florbetapir PET data to a centiloid scale. Conclusion The PET Core has demonstrated a variety of methods for the standardization of biomarkers such as florbetapir PET in a multicenter setting.
Summary Background The biomarker model of Alzheimer's disease postulates a dynamic sequence of amyloidosis, neurodegeneration, and cognitive decline as an individual progresses from preclinical ...Alzheimer's disease to dementia. Despite supportive evidence from cross-sectional studies, verification with long-term within-individual data is needed. Methods For this prospective cohort study, carriers of autosomal dominant Alzheimer's disease mutations (aged ≥21 years) were recruited from across the USA through referrals by physicians or from affected families. People with mutations in PSEN1, PSEN2 , or APP were assessed at the University of Pittsburgh Alzheimer's Disease Research Center every 1–2 years, between March 23, 2003, and Aug 1, 2014. We measured global cerebral amyloid β (Aβ) load using11 C-Pittsburgh Compound-B PET, posterior cortical metabolism with18 F-fluorodeoxyglucose PET, hippocampal volume (age and sex corrected) with T1-weighted MRI, verbal memory with the ten-item Consortium to Establish a Registry for Alzheimer's Disease Word List Learning Delayed Recall Test, and general cognition with the Mini Mental State Examination. We estimated overall biomarker trajectories across estimated years from symptom onset using linear mixed models, and compared these estimates with cross-sectional data from cognitively normal control individuals (age 65–89 years) who were negative for amyloidosis, hypometabolism, and hippocampal atrophy. In the mutation carriers who had the longest follow-up, we examined the within-individual progression of amyloidosis, metabolism, hippocampal volume, and cognition to identify progressive within-individual changes (a significant change was defined as an increase or decrease of more than two Z scores standardised to controls). Findings 16 people with mutations in PSEN1, PSEN2 , or APP , aged 28–56 years, completed between two and eight assessments (a total of 83 assessments) over 2–11 years. Significant differences in mutation carriers compared with controls (p<0·01) were detected in the following order: increased amyloidosis (7·5 years before expected onset), decreased metabolism (at time of expected onset), decreased hippocampal volume and verbal memory (7·5 years after expected onset), and decreased general cognition (10 years after expected onset). Among the seven participants with longest follow-up (seven or eight assessments spanning 6–11 years), three individuals had active amyloidosis without progressive neurodegeneration or cognitive decline, two amyloid-positive individuals showed progressive neurodegeneration and cognitive decline without further progressive amyloidosis, and two amyloid-positive individuals showed neither active amyloidosis nor progressive neurodegeneration or cognitive decline. Interpretation Our results support amyloidosis as the earliest component of the biomarker model in autosomal dominant Alzheimer's disease. Our within-individual examination suggests three sequential phases in the development of autosomal dominant Alzheimer's disease—active amyloidosis, a stable amyloid-positive period, and progressive neurodegeneration and cognitive decline—indicating that Aβ accumulation is largely complete before progressive neurodegeneration and cognitive decline occur. These findings offer supportive evidence for efforts to target early Aβ deposition for secondary prevention in individuals with autosomal dominant Alzheimer's disease. Funding National Institutes of Health and Howard Hughes Medical Institute.
•Successful reward learning is associated with elevated striatal dopamine release.•Improvements are driven by the reliable use of task-optimal learning rates.•Optimal learning is supported by ...cortical activation during reward expectation.
Converging evidence from both human neuroimaging and animal studies has supported a model of mesolimbic processing underlying reward learning behaviors, based on the computation of reward prediction errors. However, competing evidence supports human dopamine signaling in the basal ganglia as also contributing to the generation of higher order learning heuristics. Here, we present data from a large (N = 81, 18–30yo), multi-modal neuroimaging study using simultaneously acquired task fMRI, affording temporal resolution of reward system function, and PET imaging with 11CRaclopride (RAC), assessing striatal dopamine (DA) D2/3 receptor binding, during performance of a probabilistic reward learning task. Both fMRI activation and PET DA measures showed ventral striatum involvement for signaling rewards. However, greater DA release was uniquely associated with learning strategies (i.e., learning rates) that were more task-optimal within the best fitting reinforcement learning model. This DA response was associated with BOLD activation of a network of regions including anterior cingulate cortex, medial prefrontal cortex, thalamus and posterior parietal cortex, primarily during expectation, rather than prediction error, task epochs. Together, these data provide novel, human in vivo evidence that striatal dopaminergic signaling interacts with a network of cortical regions to generate task-optimal learning strategies, rather than representing reward outcomes in isolation.
Several autopsy studies recognize the locus coeruleus (LC) as the initial site of hyperphosphorylated TAU aggregation, and as the number of LC neurons harboring TAU increases, TAU pathology emerges ...throughout the cortex. By conjointly using dedicated MRI measures of LC integrity and TAU and amyloid PET imaging, we aimed to address the question whether in vivo LC measures relate to initial cortical patterns of Alzheimer’s disease (AD) fibrillar proteinopathies or cognitive dysfunction in 174 cognitively unimpaired and impaired older individuals with longitudinal cognitive measures. To guide our interpretations, we verified these associations in autopsy data from 1524 Religious Orders Study and Rush Memory and Aging Project and 2145 National Alzheimer’s Coordinating Center cases providing three different LC measures (pigmentation, tangle density, and neuronal density), Braak staging, β-amyloid, and longitudinal cognitive measures. Lower LC integrity was associated with elevated TAU deposition in the entorhinal cortex among unimpaired individuals consistent with postmortem correlations between LC tangle density and successive Braak staging. LC pigmentation ratings correlated with LC neuronal density but not with LC tangle density and were particularly worse at advanced Braak stages. In the context of elevated β-amyloid, lower LC integrity and greater cortical tangle density were associated with greater TAU burden beyond the medial temporal lobe and retrospective memory decline. These findings support neuropathologic data in which early LC TAU accumulation relates to disease progression and identify LC integrity as a promising indicator of initial AD-related processes and subtle changes in cognitive trajectories of preclinical AD.
Fibrillar amyloid-beta (Aβ) is found in the brains of many cognitively normal older people. Whether or not this reflects a predisposition to Alzheimer's disease (AD) is unknown. We used Pittsburgh ...Compound B (PiB) PET to characterize the relationship between fibrillar Aβ burden and this predisposition in cognitively normal older people at 3 mean levels of genetic risk for AD. Dynamic PiB PET scans, the Logan method, statistical parametric mapping, and automatically labeled regions of interest (ROIs) were used to characterize and compare cerebral-to-cerebellar PIB distribution volume ratios, reflecting fibrillar Aβ burden, in 28 cognitively normal persons (mean age, 64 years) with a reported family history of AD and 2 copies, 1 copy, and no copies of the apolipoprotein E (APOE) ε4 allele. The 8 ε4 homozygotes, 8 heterozygotes, and 12 noncarriers did not differ significantly in terms of age, sex, or cognitive scores. Fibrillar Aβ was significantly associated with APOE ε4 carrier status and ε4 gene dose in AD-affected mean cortical, frontal, temporal, posterior cingulate-precuneus, parietal, and basal ganglia ROIs, and was highest in an additional homozygote who had recently developed mild cognitive impairment. These findings suggest that fibrillar Aβ burden in cognitively normal older people is associated with APOE ε4 gene dose, the major genetic risk factor for AD. Additional studies are needed to track fibrillar Aβ accumulation in persons with different kinds and levels of AD risk; to determine the extent to which fibrillar Aβ, alone or in combination with other biomarkers and risk factors, predicts rates of cognitive decline and conversion to clinical AD; and to establish the role of fibrillar Aβ imaging in primary prevention trials.
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