Abstract Use of biomarkers in the detection of early and preclinical Alzheimer's disease (AD) has become of central importance following publication of the NIA-Alzheimer's Association revised ...criteria for the diagnosis of AD, mild cognitive impairment (MCI) and preclinical AD. The use of in vivo amyloid imaging agents, such a Pi ttsburgh Compound- B and markers of neurodegeneration, such as f luoro-2- d eoxy-D- g lucose (FDG) is able to detect early AD pathological processes and subsequent neurodegeneration. Imaging with PiB and FDG thus has many potential clinical benefits: early or perhaps preclinical detection of disease and accurately distinguishing AD from dementias of other etiologies in patients presenting with mild or atypical symptoms or confounding comorbidities in which the diagnostic distinction is difficult to make clinically. From a research perspective, this allows us to study relationships between amyloid pathology and changes in cognition, brain structure, and function across the continuum from normal aging to MCI to AD. The present review focuses on use of PiB and FDG-PET and their relationship to one another.
This study compared the effectiveness of the Specific Carbohydrate Diet (SCD) to the Mediterranean diet (MD) as treatment for Crohn’s disease (CD) with mild to moderate symptoms.
Adult patients with ...CD and with mild-to-moderate symptoms were randomly assigned 1:1 to consume the MD or SCD for 12 weeks. For the first 6 weeks, participants received prepared meals and snacks according to their assigned diet. After 6 weeks, participants were instructed to follow the diet independently. The primary outcome was symptomatic remission at week 6. Key secondary outcomes at week 6 included fecal calprotectin (FC) response (FC <250 μg/g and reduction by >50% among those with baseline FC >250 μg/g) and C-reactive protein (CRP) response (high-sensitivity CRP <5 mg/L and >50% reduction from baseline among those with high-sensitivity CRP >5 mg/L).
The study randomized 194 patients, and 191 were included in the efficacy analyses. The percentage of participants who achieved symptomatic remission at week 6 was not superior with the SCD (SCD, 46.5%; MD, 43.5%; P = .77). FC response was achieved in 8 of 23 participants (34.8%) with the SCD and in 4 of 13 participants (30.8%) with the MD (P = .83). CRP response was achieved in 2 of 37 participants (5.4%) with the SCD and in 1 of 28 participants (3.6%) with the MD (P = .68).
The SCD was not superior to the MD to achieve symptomatic remission, FC response, and CRP response. CRP response was uncommon. Given these results, the greater ease of following the MD and other health benefits associated with the MD, the MD may be preferred to the SCD for most patients with CD with mild to moderate symptoms. ClinicalTrials.gov Identifier: NCT03058679
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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.
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 Aβ pathology in vivo and marks a major advancement in understanding the role of Aβ 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.
•The development of fluid and PET biomarkers for Alzheimer's disease (AD), marks a major advancement in understanding the role of Aβ in AD.•Sensitive, specific and robust biomarkers to identify brain amyloidosis are central in AD research.•This review discusses we discuss fluid and PET biomarkers for Aβ and their application.
The objective of this study was to evaluate amyloid β (Aβ) deposition patterns in different groups of cerebral β amyloidosis: (1) nondemented with amyloid precursor protein overproduction (Down ...syndrome); (2) nondemented with abnormal processing of amyloid precursor protein (preclinical autosomal dominant Alzheimer disease); (3) presumed alteration in Aβ clearance with clinical symptoms (late-onset AD); and (4) presumed alterations in Aβ clearance (preclinical AD).
We performed whole-brain voxelwise comparison of cerebral Aβ between 23 Down syndrome, 10 preclinical autosomal dominant Alzheimer disease, 17 late-onset AD, and 16 preclinical AD subjects, using Pittsburgh Compound B–positron emission tomography.
We found both Down syndrome and preclinical autosomal dominant Alzheimer disease shared a distinct pattern of increased bilateral striatal and thalamic Aβ deposition compared to late-onset AD and preclinical AD.
Disorders associated with early-life alterations in amyloid precursor protein production or processing are associated with a distinct pattern of early striatal fibrillary Aβ deposition before significant cognitive impairment. A better understanding of this unique pattern could identify important mechanisms of Aβ deposition and possibly important targets for early intervention.
•RAVEL substantially improved the reproducibility of image intensities.•ComBat is preferred over RAVEL and the RAVEL-ComBat combination in terms of regional level harmonization due to more consistent ...harmonization across subjects and image-derived measures.•RAVEL and ComBat substantially reduced bias compared to analysis of RAW images, but RAVEL also resulted in larger variance.•The larger root mean square deviation (RMSD) of RAVEL compared to ComBat is due mainly to its larger variance.
Modern neuroimaging studies frequently combine data collected from multiple scanners and experimental conditions. Such data often contain substantial technical variability associated with image intensity scale (image intensity scales are not the same in different images) and scanner effects (images obtained from different scanners contain substantial technical biases). Here we evaluate and compare results of data analysis methods without any data transformation (RAW), with intensity normalization using RAVEL, with regional harmonization methods using ComBat, and a combination of RAVEL and ComBat. Methods are evaluated on a unique sample of 16 study participants who were scanned on both 1.5T and 3T scanners a few months apart. Neuroradiological evaluation was conducted for 7 different regions of interest (ROI's) pertinent to Alzheimer's disease (AD). Cortical measures and results indicate that: (1) RAVEL substantially improved the reproducibility of image intensities; (2) ComBat is preferred over RAVEL and the RAVEL-ComBat combination in terms of regional level harmonization due to more consistent harmonization across subjects and image-derived measures; (3) RAVEL and ComBat substantially reduced bias compared to analysis of RAW images, but RAVEL also resulted in larger variance; and (4) the larger root mean square deviation (RMSD) of RAVEL compared to ComBat is due mainly to its larger variance.
Adults with Down syndrome (DS) are predisposed to Alzheimer's disease (AD) and reveal early amyloid beta (Aβ) pathology in the brain. Positron emission tomography (PET) provides an in vivo measure of ...Aβ throughout the AD continuum. Due to the high prevalence of AD in DS, there is need for longitudinal imaging studies of Aβ to better characterize the natural history of Aβ accumulation, which will aid in the staging of this population for clinical trials aimed at AD treatment and prevention.
Adults with DS (N = 79; Mean age (SD) = 42.7 (7.28) years) underwent longitudinal C-11Pittsburgh compound B (PiB) PET. Global Aβ burden was quantified using the amyloid load metric (AβL). Modeled PiB images were generated from the longitudinal AβL data to visualize which regions are most susceptible to Aβ accumulation in DS. AβL change was evaluated across Aβ(-), Aβ-converter, and Aβ(+) groups to assess longitudinal Aβ trajectories during different stages of AD-pathology progression. AβL change values were used to identify Aβ-accumulators within the Aβ(-) group prior to reaching the Aβ(+) threshold (previously reported as 20 AβL) which would have resulted in an Aβ-converter classification. With knowledge of trajectories of Aβ(-) accumulators, a new cutoff of Aβ(+) was derived to better identify subthreshold Aβ accumulation in DS. Estimated sample sizes necessary to detect a 25% reduction in annual Aβ change with 80% power (alpha 0.01) were determined for different groups of Aβ-status.
Modeled PiB images revealed the striatum, parietal cortex and precuneus as the regions with earliest detected Aβ accumulation in DS. The Aβ(-) group had a mean AβL change of 0.38 (0.58) AβL/year, while the Aβ-converter and Aβ(+) groups had change of 2.26 (0.66) and 3.16 (1.34) AβL/year, respectively. Within the Aβ(-) group, Aβ-accumulators showed no significant difference in AβL change values when compared to Aβ-converter and Aβ(+) groups. An Aβ(+) cutoff for subthreshold Aβ accumulation was derived as 13.3 AβL. The estimated sample size necessary to detect a 25% reduction in Aβ was 79 for Aβ(-) accumulators and 59 for the Aβ-converter/Aβ(+) group in DS.
Longitudinal AβL changes were capable of distinguishing Aβ accumulators from non-accumulators in DS. Longitudinal imaging allowed for identification of subthreshold Aβ accumulation in DS during the earliest stages of AD-pathology progression. Detection of active Aβ deposition evidenced by subthreshold accumulation with longitudinal imaging can identify DS individuals at risk for AD development at an earlier stage.
Objective
We utilized the amyloid imaging ligand Pittsburgh Compound B (PiB) to determine the presence of Alzheimer's disease (AD) pathology in different mild cognitive impairment (MCI) subtypes and ...to relate increased PiB binding to other markers of early AD and longitudinal outcome.
Methods
Twenty‐six patients with MCI (13 single‐domain amnestic‐MCI a‐MCI, 6 multidomain a‐MCI, and 7 nonamnestic MCI) underwent PiB imaging. Twenty‐three had clinical follow‐up (21.2 ± 16.0 standard deviation months) subsequent to their PiB scan.
Results
Using cutoffs established from a control cohort, we found that 14 (54%) patients had increased levels of PiB retention and were considered “amyloid‐positive.” All subtypes were associated with a significant proportion of amyloid‐positive patients (6/13 single‐domain a‐MCI, 5/6 multidomain a‐MCI, 3/7 nonamnestic MCI). There were no obvious differences in the distribution of PiB retention in the nonamnestic MCI group. Predictors of conversion to clinical AD in a‐MCI, including poorer episodic memory, and medial temporal atrophy, were found in the amyloid‐positive relative to amyloid‐negative a‐MCI patients. Longitudinal follow‐up demonstrated 5 of 13 amyloid‐positive patients, but 0 of 10 amyloid‐negative patients, converted to clinical AD. Further, 3 of 10 amyloid‐negative patients “reverted to normal.”
Interpretation
These data support the notion that amyloid‐positive patients are likely to have early AD, and that the use of amyloid imaging may have an important role in determining which patients are likely to benefit from disease‐specific therapies. In addition, our data are consistent with longitudinal studies that suggest a significant percentage of all MCI subtypes will develop AD. Ann Neurol 2009;65:557–568
An important research application of amyloid imaging with positron emission tomography (PET) is detection of the earliest evidence of fibrillar amyloid-beta (Aβ) deposition. Use of amyloid PET for ...this purpose, requires a reproducible method for defining a cutoff that separates individuals with no significant Aβ deposition from those in which Aβ deposition has begun. We previously reported the iterative outlier approach (IO) for the analysis of Pittsburgh Compound-B (PiB) PET data. Developments in amyloid imaging since the initial report of IO have led us to re-examine the generalizability of this method. IO was developed using full-dynamic atrophy-corrected PiB PET data obtained from a group of control subjects with a fairly distinct separation between PiB-positive PiB(+) and PiB-negative PiB(−) subjects.
We tested the performance of IO using late-summed tissue ratio data with atrophy correction or with an automated template method without atrophy correction and tested the robustness of the method when applied to a cohort of older subjects in which separation between PiB(+) and PiB(−) subjects was not so distinct.
The IO method did not perform consistently across analyses and performed particularly poorly when separation was less clear. We found that a sparse k-means (SKM) cluster analysis approach performed significantly better; performing more consistently across methods and subject cohorts. We also compared SKM to a consensus visual read approach and found very good correspondence.
The visual read and SKM methods, applied together, may optimize the identification of early Aβ deposition. These methods have the potential to provide a standard approach to the detection of PiB-positivity that is generalizable across centers.
► Limitations of the iterative outlier method for Aβ-positive cutoffs ► Use of sparse k-means as a method for identification of Aβ-positive cutoffs ► Comparison of the above objective methods to visual reads shows good agreement. ► A combination of methods may be the best approach to identify early Aβ.
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