The Association of Multimorbidity With Preclinical AD Stages and SNAP in Cognitively Unimpaired Persons.
ABSTRACT: BACKGROUND:Multimorbidity (defined as ≥2 chronic conditions) has been associated with increased risk of mild cognitive impairment and cross-sectionally with imaging biomarkers of neurodegeneration in cognitively unimpaired persons aged ≥70 years. Its association with preclinical Alzheimer's disease stages has not been studied in detail yet. The objective of the study was to assess the cross-sectional association of multimorbidity with preclinical Alzheimer's disease stages and suspected non-amyloid pathophysiology in cognitively unimpaired participants of the Mayo Clinic Study of Aging (≥50 years of age). METHODS:The study included 1,535 cognitively unimpaired participants with multimorbidity, 11C-PiB positron emission topography and magnetic resonance imaging data available. Abnormal (elevated) 11C-PiB-positron emission topography retention ratio (A+; standardized uptake value ratio >1.42) and abnormal (reduced) Alzheimer's disease signature cortical thickness (N+; <2.67 mm) were used to define biomarker combinations (A-N-, A+N-, A-N+, A+N+). Chronic medical conditions were ascertained by using the Rochester Epidemiology Project medical records linkage system and International Classification of Diseases criteria. Cross-sectional associations were examined using multinomial logistic regression models adjusting for age, sex, education, and apolipoprotein E ɛ4 allele status. RESULTS:Frequency of A+, N+, A+N+, and A-N+ biomarker groups increased significantly with increasing number of chronic conditions. Multimorbidity was significantly associated with A+N+ (vs A-N-; odds ratio, 1.76, 95% confidence interval 1.02, 2.90) and A-N+ (vs A-N-; odds ratio, 2.16, 95% confidence interval 1.47, 3.18). There was a dose-response relationship between increasing number of chronic conditions (eg, 0-1, 2-3, and 4+) and the odds of A+N+ and A-N+ (vs A-N-). CONCLUSIONS:Multimorbidity was associated with biomarker combinations that included neurodegeneration with or without elevated amyloid deposition (ie, A-N+, A+N+). The associations should be validated in longitudinal studies.
Project description:This study investigated differences in retrospective cognitive trajectories between amyloid and tau PET biomarker stratified groups in initially cognitively unimpaired participants sampled from the Wisconsin Registry for Alzheimer's Prevention. One hundred and sixty-seven initially unimpaired individuals (baseline age 59 ± 6 years; 115 females) were stratified by elevated amyloid-? and tau status based on 11C-Pittsburgh compound B (PiB) and 18F-MK-6240 PET imaging. Mixed effects models were used to determine if longitudinal cognitive trajectories based on a composite of cognitive tests including memory and executive function differed between biomarker groups. Secondary analyses investigated group differences for a variety of cross-sectional health and cognitive tests, and associations between 18F-MK-6240, 11C-PiB, and age. A significant group × age interaction was observed with post hoc comparisons indicating that the group with both elevated amyloid and tau pathophysiology were declining approximately three times faster in retrospective cognition compared to those with just one or no elevated biomarkers. This result was robust against various thresholds and medial temporal lobe regions defining elevated tau. Participants were relatively healthy and mostly did not differ between biomarker groups in health factors at the beginning or end of study, or most cognitive measures at study entry. Analyses investigating association between age, MK-6240 and PiB indicated weak associations between age and 18F-MK-6240 in tangle-associated regions, which were negligible after adjusting for 11C-PiB. Strong associations, particularly in entorhinal cortex, hippocampus and amygdala, were observed between 18F-MK-6240 and global 11C-PiB in regions associated with Braak neurofibrillary tangle stages I-VI. These results suggest that the combination of pathological amyloid and tau is detrimental to cognitive decline in preclinical Alzheimer's disease during late middle-age. Within the Alzheimer's disease continuum, middle-age health factors likely do not greatly influence preclinical cognitive decline. Future studies in a larger preclinical sample are needed to determine if and to what extent individual contributions of amyloid and tau affect cognitive decline. 18F-MK-6240 shows promise as a sensitive biomarker for detecting neurofibrillary tangles in preclinical Alzheimer's disease.
Project description:Amyloid-? (A?) deposition as seen on PET using an A?-binding agent is a critical diagnostic biomarker for Alzheimer disease (AD). Some reports suggest using white matter (WM) as a reference region for quantification of serial A? PET studies; however, nonspecific WM retention in A? PET in people with dementia or cognitively unimpaired (CU) has been widely reported and is poorly understood. Methods: To investigate the suitability of WM as a reference region and the factors affecting WM 11C-Pittsburgh compound B (11C-PiB) uptake variability, we conducted a retrospective study on 2 large datasets: a longitudinal study of participants (n = 577) who were CU, had mild cognitive impairment, or had dementia likely due to AD; and a cross-sectional study of single-scan PET imaging in CU subjects (n = 1,349). In the longitudinal study, annual changes in WM 11C-PiB uptake were assessed, and in the cross-sectional study, WM 11C-PiB uptake was assessed relative to subject age. Results: Overall, we found that WM 11C-PiB uptake showed age-related increases, which varied with the WM regions selected. Further, variable annual WM 11C-PiB uptake changes were seen with different gray matter (GM) 11C-PiB baseline uptake levels. Conclusion: WM binding increases with age and varies with GM 11C-PiB. These correlations should be considered when using WM for normalization in 11C-PiB PET studies. The cerebellar crus1+crus2 showed no increase with age and cerebellar GM+WM showed minimal increase, supporting their use as reference regions for cross-sectional studies comparing wide age spans. In longitudinal studies, the increase in WM uptake may be minimal in the short-term and thus using WM as a reference region in these studies seems reasonable. However, as participants age, the findings may be affected by changes in WM uptake. Changes in WM 11C-PiB uptake may relate to disease progression, warranting examination of the causes of WM 11C-PiB uptake.
Project description:In 1164 cognitively unimpaired persons, aged 50-95 years, from the population-based Mayo Clinic Study of Aging, we examined the relationships of baseline cognition and cognitive changes across the full range of cortical thickness of an Alzheimer signature region of interest and global ?-amyloid levels measured by Pittsburgh compound B positron emission tomography (PIB PET) standardized uptake value ratio (SUVR). In machine-learning models accounting for both biomarkers simultaneously, worsening biomarker values were additive and associated with lower baseline global cognition and greater subsequent decline in global cognition. Associations between Alzheimer's disease signature cortical thickness or PIB PET ?-amyloid SUVR and baseline cognition were mainly linear. Lower Alzheimer's disease signature cortical thickness values across the entire range of thickness predicted future decline in global cognitive scores, demonstrating its close relationship to cognitive functioning. PIB PET ?-amyloid SUVR also predicted cognitive decline across its full range, even when cortical thickness was accounted for. PIB PET ?-amyloid's relationship to cognitive decline was nonlinear, more prominent at lower ?-amyloid levels and less prominent at higher ?-amyloid levels.
Project description:Objective:To investigate the associations of Pittsburgh compound-B (PiB) uptake in white matter hyperintensities (WMH) and normal appearing white matter (NAWM) with white matter (WM) integrity measured with DTI and cognitive function in cognitively unimpaired older adults. Methods:Cognitively unimpaired older adults from the population-based Mayo Clinic Study of Aging (n = 537, age 65-95) who underwent both PiB PET and DTI were included. The associations of WM PiB standard uptake value ratio (SUVr) with fractional anisotropy (FA) and mean diffusivity (MD) in the WMH and NAWM were tested after adjusting for age. The associations of PiB SUVr with cognitive function z-scores were tested after adjusting for age and global cortical PiB SUVr. Results:The WMH PiB SUVr was lower than NAWM PiB SUVr (P < 0.001). In the WMH, lower PiB SUVr correlated with lower FA (r = 0.21, P < 0.001), and higher MD (r = -0.31, P < 0.001). In the NAWM, lower PiB SUVr only correlated with higher MD (r = -0.10, P = 0.02). Both in the WMH and NAWM, lower PiB SUVr was associated with lower memory, language, and global cognitive function z-scores after adjusting for age and global cortical PiB SUVr. Interpretation:Reduced PiB uptake in the WMH is associated with a loss of WM integrity and cognitive function after accounting for the global cortical PiB uptake, suggesting that WM PiB uptake may be an early biomarker of WM integrity that precedes cognitive impairment in older adults. When using WM as a reference region in cross-sectional analysis of PiB SUVr, individual variability in WMH volume as well as age should be considered.
Project description:Amyloid-beta plaques are a hallmark of Alzheimer's disease (AD) that can be assessed by amyloid imaging (e.g., Pittsburgh B compound [PiB]) and summarized as a scalar value. Summary values may have clinical utility but are an average over many regions of interest, potentially obscuring important topography. This study investigates the longitudinal evolution of amyloid topographies in cognitively normal older adults who had normal (N = 131) or abnormal (N = 26) PiB scans at baseline. At 3 years follow-up, 16 participants with a previously normal PiB scan had conversion to PiB scans consistent with preclinical AD. We investigated the multivariate relationship (canonical correlation) between baseline and follow-up PiB topographies. Furthermore, we used penalized regression to investigate the added information derived from PiB topography compared to summary measures. PiB accumulation can be local, that is, a topography predicting the same topography in the future, and/or distributed, that is, one topography predicting another. Both local and distributed PiB accumulation was associated with conversion of PiB status. Additionally, elements of the multivariate topography, and not the commonly used summary scalar, correlated with future PiB changes. Consideration of the entire multivariate PiB topography provides additional information regarding the development of amyloid-beta pathology in very early preclinical AD.
Project description:To date, most diagnostic imaging comparisons between amyloid labelling ligands and other imaging modalities have been between the use of amyloid labelling ligand (11)C Pittsburgh Compound B (PiB) and FDG-PET. Our objectives were to compare cognitive performance and diagnostic group-wise discrimination between cognitively normal, amnestic mild cognitive impairment (MCI) and Alzheimer's disease subjects with MRI-based measures of hippocampal volume and PiB retention, and secondly to evaluate the topographic distribution of PiB retention and grey matter loss using 3D voxel-wise methods. Twenty cognitively normal, 17 amnestic MCI and 8 probable Alzheimer's disease subjects were imaged with both MRI and PiB. PiB retention was quantified as the ratio of uptake in cortical to cerebellar regions of interest (ROIs) 40-60 min post-injection. A global cortical PiB retention summary measure was derived from six cortical ROIs. Statistical parametric mapping (SPM) and voxel-based morphometry (VBM) were used to evaluate PiB retention and grey matter loss on a 3D voxel-wise basis. Alzheimer's disease subjects had high global cortical PiB retention and low hippocampal volume; most cognitively normal subjects had low PiB retention and high hippocampal volume; and on average amnestic MCI subjects were intermediate on both PiB and hippocampal volume. A target-to-cerebellar ratio of 1.5 was used to designate subjects with high or low PiB cortical retention. All Alzheimer's disease subjects fell above this ratio, as did 6 out of 20 cognitively normal subjects and 9 out of 17 MCI subjects, indicating bi-modal PiB retention in the latter two groups. Interestingly, we found no consistent differences in learning and memory performance between high versus low PiB cognitively normal or amnestic MCI subjects. The SPM/VBM voxel-wise comparisons of Alzheimer's disease versus cognitively normal subjects provided complementary information in that clear and meaningful similarities and differences in topographical distribution of amyloid deposition and grey matter loss were shown. The frontal lobes had high PiB retention with little grey matter loss, anteromedial temporal areas had low PiB retention with significant grey matter loss, whereas lateral temporoparietal association cortex displayed both significant PiB retention and grey matter loss. A voxel-wise SPM conjunction analysis revealed that subjects with high PiB retention shared a common PiB retention topographical pattern regardless of clinical category, and this matched that of amyloid plaque distribution from autopsy studies of Alzheimer's disease. Both global cortical PiB retention and hippocampal volumes demonstrated significant correlation in the expected direction with cognitive testing performance; however, correlations were stronger with MRI than PiB. Pair-wise inter-group diagnostic separation was significant for all group-wise pairs for both PiB and hippocampal volume with the exception of the comparison of cognitively normal versus amnestic MCI, which was not significant for PiB. PiB and MRI provided complementary information such that clinical diagnostic classification using both methods was superior to using either in isolation.
Project description:BACKGROUND:A decreased concentration of beta amyloid (1-42) (Abeta42) has consistently been found in the cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD) and is considered a diagnostic biomarker. However, it is not clear to which extent CSF Abeta42 levels are reflective of cerebral pathology in AD. The aim of the study was to determine the association between cerebral amyloid plaque load, as measured by means of the positron emission tomography (PET) tracer carbon-11-labeled Pittsburgh Compound B ([11C]PiB) and CSF Abeta42 in AD. METHODS:A group of 30 patients with probable AD, as defined by established clinical criteria and by an AD-typical pattern of tracer uptake in fluorine-18-labeled fluorodeoxyglucose ([18F]FDG) PET, were included. In all patients, [11C]PiB PET and CSF analysis were performed. The association between amyloid load and CSF Abeta42 levels was examined in three different ways: by linear regression analysis using an overall [11C]PiB value for the entire cerebrum, by correlation analyses using [11C]PiB measurements in anatomically defined regions of interest, and by voxel-based regression analyses. RESULTS:All patients showed a positive [11C]PiB scan demonstrating amyloid deposition. Linear regression analysis revealed a significant inverse correlation between the overall [11C]PiB uptake and CSF Abeta42 levels. Voxel-based regression and regional correlation analyses did not attain statistical significance after correction for multiple comparisons. Numerically, correlation coefficients were higher in brain regions adjacent to CSF spaces. CONCLUSIONS:The study demonstrates a moderate linear negative association between cerebral amyloid plaque load and CSF Abeta42 levels in AD patients in vivo and suggests possible regional differences of the association.
Project description:Purpose:Recent study shows that blood-derived amyloid-beta (A?) can induce cerebral amyloidosis and is involved in the pathogenesis of Alzheimer's disease (AD). The vast majority of blood A? is generated from platelet. Whether blood A? levels are associated with the count of platelets remains unknown. Methods:58 clinically diagnosed AD patients, 18 11C-PIB-PET diagnosed AD patients, and 61 age- and gender-matched cognitively normal controls were included to analyze the correlation of plasma A? levels with platelet count. 13 AD patients and 40 controls with cerebrospinal fluid (CSF) samples were included to further analyze the correlation of CSF A? levels with platelet count. A?40 and A?42 levels in plasma and CSF were measured by ELISA kits. Results:The plasma A?42 level was positively correlated with platelet count in both AD patients and control group, especially in AD patients with positive PIB-PET, while there was no correlation as to A?40. The CSF A? levels also had no significant correlation with platelet count. Conclusion:It suggests that platelets may be involved in the pathogenesis of AD and become a potential peripheral biomarker for AD.
Project description:Recently, we developed a benzofuran derivative for the imaging of ?-amyloid plaques, 5-(5-(2-(2-(2-18F-fluoroethoxy)ethoxy)ethoxy)benzofuran-2-yl)-N-methylpyridin-2-amine (18F-FPYBF-2) (Ono et al., J Med Chem 54:2971-9, 2011). The aim of this study was to assess the feasibility of 18F-FPYBF-2 as an amyloid imaging PET tracer in a first clinical study with healthy volunteers and patients with various dementia and in comparative dual tracer study using 11C-Pittsburgh Compound B (11C-PiB).61 healthy volunteers (age: 53.7?±?13.1 years old; 19 male and 42 female; age range 24-79) and 55 patients with suspected dementia [Alzheimer's Disease (AD); early AD: n?=?19 and moderate stage AD: n?=?8, other dementia: n?=?9, mild cognitive impairment (MCI): n?=?16, cognitively normal: n?=?3] for first clinical study underwent static head PET/CT scan using 18 F - FPYBF-2 at 50-70 min after injection. 13 volunteers and 14 patients also underwent dynamic PET scan at 0-50 min at the same instant. 16 subjects (volunteers: n?=?5, patients with dementia: n?=?11) (age: 66.3?±?14.2 years old; 10 males and 6 females) were evaluated for comparative study (50-70 min after injection) using 18F-FPYBF-2 and 11C-PiB on separate days, respectively. Quantitative analysis of mean cortical uptake was calculated using Mean Cortical Index of SUVR (standardized uptake value ratio) based on the established method for 11C-PiB analysis using cerebellar cortex as control.Studies with healthy volunteers showed that 18F-FPYBF-2 uptake was mainly observed in cerebral white matter and that average Mean Cortical Index at 50-70 min was low and stable (1.066?±?0.069) basically independent from age or gender. In patients with AD, 18F-FPYBF-2 uptake was observed both in cerebral white and gray matter, and Mean Cortical Index was significantly higher (early AD: 1.288?±?0.134, moderate AD: 1.342?±?0.191) than those of volunteers and other dementia (1.018?±?0.057). In comparative study, the results of 18F-FPYBF-2 PET/CT were comparable with those of 11C-PiB, and the Mean Cortical Index (18F-FPYBF-2: 1.173?±?0.215; 11C-PiB: 1.435?±?0.474) showed direct proportional relationship with each other (p?<?0.0001).Our first clinical study suggest that 18F-FPYBF-2 is a useful PET tracer for the evaluation of ?-amyloid deposition and that quantitative analysis of Mean Cortical Index of SUVR is a reliable diagnostic tool for the diagnosis of AD.
Project description:Beta-amyloid (A?) plaque deposition is a key feature of Alzheimer's disease (AD), and occurs years before the onset of symptoms. A? plaque deposition has been shown to be present in ~30% of cognitively normal older adults using amyloid C-11 labeled Pittsburgh Compound B (11C-PiB) Positron Emission Tomography (PET) imaging. Prior studies have reported a link between reduced vestibular function and poorer cognition in healthy older adults. It is unknown whether vestibular impairment occurs in association with AD pathology among individuals in the preclinical phase of AD, which could contribute to the observed association between vestibular and cognitive function in healthy older adults. Using the Baltimore Longitudinal Study of Aging (BLSA), we analyzed the association between a comprehensive set of vestibular function measures and PiB status in 98 healthy participants with a mean age of 77.3 (±8.26). We did not observe a significant relationship between any vestibular function measure and PiB status in cognitively-intact older adults in the BLSA. This finding suggests that A? deposition does not explain the observed association between reduced vestibular function and poorer cognition in healthy older adults.