Extensive cortical β-amyloid (Aβ positivity) has been linked to cognitive decline, but the clinical significance of elevations in Aβ within the negative range is unknown.
We examined amyloid and ...cognitive trajectories (memory, executive function) in 142 cognitively normal older individuals enrolled in the Alzheimer's Disease Neuroimaging Initiative who were Aβ-negative at baseline and who had at least 2
F-florbetapir PET scans over 3.9 ± 1.4 years. We determined whether Aβ accumulation was associated with longitudinal changes in memory or executive function.
Among baseline-negative individuals, florbetapir slope (mean annual increase 0.002 ± 0.008 standardized uptake value ratio units/y) was not related to age, sex, education,
status, baseline memory or executive function, temporoparietal glucose metabolism, baseline hippocampal volume, or hippocampal volume change; but it was related to higher baseline cortical florbetapir, indicating that Aβ accumulation was ongoing at baseline in those who accumulated during the study. Over the course of follow-up, 13 individuals converted to florbetapir+ and 14 nearly nonoverlapping individuals converted to mild cognitive impairment or Alzheimer disease. Amyloid accumulation among baseline-negative individuals was associated with poorer longitudinal memory performance (
= 0.019), but it was not associated with changes in executive function. Reducing the sample to individuals with at least 3 timepoints to estimate the florbetapir slope strengthened the relationship further between florbetapir accumulation and memory decline (
= 0.007).
Memory decline accompanies Aβ accumulation in otherwise healthy, Aβ-negative older adults. Amyloid increases within the negative range may represent the earliest detectable indication of pathology with domain-specific cognitive consequences.
To understand the time course of β-amyloid (Aβ) deposition in the brain, which is crucial for planning therapeutic trials of Aβ-lowering therapies in Alzheimer disease (AD).
Two samples of ...participants from the Alzheimer's Disease Neuroimaging Initiative were studied with
FFlorbetapir (FBP) Aβ PET and followed for up to 9 years. Sample A included 475 cognitively normal (CN) older people and those with mild cognitive impairment (MCI) and AD and sample B included 220 CN Aβ- individuals. We examined the trajectory of FBP over time in sample A and the incidence rate of conversion from negative to positive Aβ PET scans in sample B.
The relationship between time and brain Aβ was sigmoidal, taking 6.4 years to transition from amyloid negative to positive and another 13.9 years to the onset of MCI. Aβ deposition rates began to slow only 3.8 years after reaching the positivity threshold. The incidence rate for scan positivity was 38/1,000 person-years, and factors associated with conversion were age, baseline FBP, and being a female
ε4 carrier. Among CN Aβ- individuals, FBP slopes were associated with rates of memory decline and brain tau measured with
FFlortaucipir PET 5 years after baseline.
Lowering brain Aβ must be accomplished early in the evolution of AD. Transitions of PET scans from Aβ- to Aβ+ should be predictable, and it is reasonable to expect that lowering rates of Aβ even in early stages could produce clinically significant benefits.
Abstract The Functional Activities Questionnaire (FAQ) and Alzheimer's Disease Assessment Scale—cognitive subscale (ADAS-cog) are frequently used indices of cognitive decline in Alzheimer's disease ...(AD). The goal of this study was to compare FDG-PET and clinical measurements in a large sample of elderly subjects with memory disturbance. We examined relationships between glucose metabolism in FDG-PET regions of interest (FDG-ROIs), and ADAS-cog and FAQ scores in AD and mild cognitive impairment (MCI) patients enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Low glucose metabolism at baseline predicted subsequent ADAS-cog and FAQ decline. In addition, longitudinal glucose metabolism decline was associated with concurrent ADAS-cog and FAQ decline. Finally, a power analysis revealed that FDG-ROI values have greater statistical power than ADAS-cog to detect attenuation of cognitive decline in AD and MCI patients. Glucose metabolism is a sensitive measure of change in cognition and functional ability in AD and MCI, and has value in predicting future cognitive decline.
To examine the feasibility of using cross-sectional PET to identify cognitive decliners among β-amyloid (Aβ)-negative cognitively normal (CN) elderly adults.
We determined the highest Aβ-affected ...region by ranking baseline and accumulation rates of florbetapir-PET regions in 355 CN elderly adults using
F-florbetapir-PET from the Alzheimer's Disease Neuroimaging Initiative (ADNI). The banks of the superior temporal sulcus (BANKSSTS) were found as the highest Aβ-affected region, and Aβ positivity in this region was defined as above the lowest boundary of BANKSSTS standardized uptake value ratio of Aβ+ (ADNI-defined COMPOSITE region) CN individuals. The entire CN cohort was divided as follows: stage 0, BANKSSTS-COMPOSITE-; stage 1, BANKSSTS+COMPOSITE-; and stage 2, BANKSSTS+COMPOSITE+. Linear mixed-effect (LME) models investigated subsequent longitudinal cognitive change, and
F-flortaucipir (FTP)-PET was measured 4.8 ± 1.6 years later to track tau deposition.
LME analysis revealed that individuals in stage 1 (n = 64) and stage 2 (n = 99) showed 2.5 (
< 0.05) and 4.8 (
< 0.001) times faster memory decline, respectively, than those in stage 0 (n = 191) over >4 years of mean follow-up. Compared to stage 0, both stage 1 (
< 0.05) and stage 2 (
< 0.001) predicted higher FTP in entorhinal cortex.
Nominally Aβ- CN individuals with high Aβ in BANKSSTS are at increased risk of cognitive decline, probably showing an earlier stage of Aβ deposition. Our findings may help elucidate the association between brain Aβ accumulation and cognition in Aβ- CN cohorts.
This study provides Class II evidence that in elderly CN individuals those with high PET-identified superior temporal sulcus Aβ burden have an increased risk of cognitive decline.
Objective:
Using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) population, we examined (1) cross‐sectional relationships between amyloid deposition, hypometabolism, and cognition, ...and (2) associations between amyloid and hypometabolism measurements and longitudinal cognitive measurements.
Methods:
We examined associations between mean cortical florbetapir uptake, mean 18F‐fluorodeoxyglucose–positron emission tomography (FDG‐PET) within a set of predefined regions, and Alzhiemer's Disease Assessment Scale (ADAS‐cog) performance in 426 ADNI participants (126 normal, 162 early mild cognitive impairment EMCI, 85 late MCI LMCI, 53 Alzheimer disease AD patients). For a subset of these (76 normal, 81 LMCI) we determined whether florbetapir and FDG‐PET were associated with retrospective decline in longitudinal ADAS‐cog measurements.
Results:
Twenty‐nine percent of normal subjects, 43% of EMCI patients, 62% of LMCI patients, and 77% of AD patients were categorized as florbetapir positive. Florbetapir was negatively associated with concurrent FDG and ADAS‐cog in both MCI groups. In longitudinal analyses, florbetapir‐positive subjects in both normal and LMCI groups had greater ongoing ADAS‐cog decline than those who were florbetapir negative. However, in normal subjects, florbetapir positivity was associated with greater ADAS‐cog decline than FDG, whereas in LMCI, FDG positivity was associated with greater decline than florbetapir.
Interpretation:
Although both hypometabolism and β‐amyloid (Aβ) deposition are detectable in normal subjects and all diagnostic groups, Aβ showed greater associations with cognitive decline in normal participants. In view of the minimal cognitive deterioration overall in this group, this suggests that amyloid deposition has an early and subclinical impact on cognition that precedes metabolic changes. At moderate and later stages of disease (LMCI/AD), hypometabolism becomes more pronounced and more closely linked to ongoing cognitive decline. ANN NEUROL 2012;72:578–586
The ε4 allele of the polymorphic apolipoprotein E gene is associated with increased risk of Alzheimer's disease (AD), deposition of β-amyloid (Aβ), and reduction in cerebral glucose metabolism in ...asymptomatic people. Although ApoE4 may exert an effect on AD risk through amyloidogenic pathways, whether its effect on glucose metabolism is related to Aβ is unknown. To answer this question, we examined data from 175 cognitively normal older people (mean age, 77; 87 men, 88 women) in the Alzheimer's disease neuroimaging initiative studied concurrently with (18)Fflurodeoxyglucose (FDG) positron emission tomography measures of glucose metabolism and the radiotracer (18)Fflorbetapir, an imaging agent which labels fibrillar Aβ in vivo. Based on a threshold value of florbetapir uptake determined in separate samples, subjects were categorized as florbetapir+ or florbetapir-. Glucose metabolism was measured as a continuous variable in a group of regions of interest (ROIs) selected a priori based on their involvement in AD, and also by using a whole-brain voxelwise approach. Among this sample, 29% of subjects were florbetapir+ and 23% were ApoE4 carriers. As expected, there was a significant association between ApoE4 genotype and florbetapir positivity. Florbetapir status, however, was not significantly associated with glucose metabolism, but the ApoE4 genotype was associated with lower metabolism in both voxelwise and ROI approaches. These results show that ApoE genotype, and not aggregated fibrillar forms of Aβ, contributes to reduced glucose metabolism in aging and adds to a growing list of neural consequences of ApoE that do not appear to be related to Aβ.
Criteria for preclinical Alzheimer disease (AD) propose β-amyloid (Aβ) plaques to initiate neurodegeneration within AD-affected regions. However, some cognitively normal older individuals harbor ...neural injury similar to patients with AD, without concurrent Aβ burden. Such findings challenge the proposed sequence and suggest that Aβ-independent precursors underlie AD-typical neurodegenerative patterns. OBJECTIVE To examine relationships between Aβ and non-Aβ factors as well as neurodegeneration within AD regions in cognitively normal older adults. The study quantified neurodegenerative abnormalities using imaging biomarkers and examined cross-sectional relationships with Aβ deposition; white matter lesions (WMLs), a marker of cerebrovascular disease; and cognitive functions.
Cross-sectional study in a community-based convenience sample of 72 cognitively normal older individuals (mean SD age, 74.9 5.7 years; 48 women; mean SD 17.0 1.9 years of education) of the Berkeley Aging Cohort.
Each individual underwent a standardized neuropsychological test session, magnetic resonance imaging, and positron emission tomography scanning.
For each individual, 3 AD-sensitive neurodegeneration biomarkers were measured: hippocampal volume, glucose metabolism, and gray matter thickness, the latter 2 sampled from cortical AD-affected regions. To quantify neurodegenerative abnormalities, each biomarker was age adjusted, dichotomized into a normal or abnormal status (using cutoff thresholds derived from an independent AD sample), and summarized into 0, 1, or more than 1 abnormal neurodegenerative biomarker. Degree and topographic patterns of neurodegenerative abnormalities were assessed and their relationships with cognitive functions, WML volume, and Aβ deposition (quantified using carbon 11-labeled Pittsburgh compound B positron emission tomography).
Of our cognitively normal elderly individuals, 40% (n = 29) displayed at least 1 abnormal neurodegenerative biomarker, 26% (n = 19) of whom had no evidence of elevated Pittsburgh compound B retention. In those people who were classified as having abnormal cortical thickness, degree and topographic specificity of neurodegenerative abnormalities were similar to patients with AD. Accumulation of neurodegenerative abnormalities was related to poor memory and executive functions as well as larger WML volumes but not elevated Pittsburgh compound B retention.
Our study confirms that a substantial proportion of cognitively normal older adults harbor neurodegeneration, without Aβ burden. Associations of neurodegenerative abnormalities with cerebrovascular disease and cognitive performance indicate that neurodegenerative pathology can emerge through non-Aβ pathways within regions most affected by AD.
Tau PET has allowed for critical insights into in vivo patterns of tau accumulation and change in individuals early in the Alzheimer's disease (AD) continuum. A key methodological step in tau PET ...analyses is the selection of a reference region, but there is not yet consensus on the optimal region especially for longitudinal tau PET analyses. This study examines how reference region selection influences results related to disease stage at baseline and over time. Longitudinal flortaucipir (18F-AV1451) PET scans were examined using several common reference regions (e.g., eroded subcortical white matter, inferior cerebellar gray matter) in 62 clinically unimpaired amyloid negative (CU A-) individuals, 73 CU amyloid positive (CU A+) individuals, and 64 amyloid positive individuals with mild cognitive impairment (MCI A+) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Cross-sectionally, both reference regions resulted in robust group differences between CU A-, CU A+, and MCI A+ groups, along with significant associations with CSF phosphorylated tau (pTau-181). However, these results were more focally specific and akin to Braak Staging when using eroded white matter, whereas effects with inferior cerebellum were globally distributed across most cortical regions. Longitudinally, utilization of eroded white matter revealed significant accumulation greater than zero across more regions whereas change over time was diminished using inferior cerebellum. Interestingly, the inferior temporal target region seemed most robust to reference region selection with expected cross-sectional and longitudinal signal across both reference regions. With few exceptions, baseline tau did not significantly predict longitudinal change in tau in the same region regardless of reference region. In summary, reference region selection deserves further evaluation as this methodological step may lead to disparate findings. Inferior cerebellar gray matter may be more sensitive to cross-sectional flortaucipir differences, whereas eroded subcortical white matter may be more sensitive for longitudinal analyses examining regional patterns of change.
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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.
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