Dynamic relationships between age, amyloid-β deposition, and glucose metabolism link to the regional vulnerability to Alzheimer's disease.

SEE HANSSON AND GOURAS DOI101093/AWW146 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Although some brain regions such as precuneus and lateral temporo-parietal cortex have been shown to be more vulnerable to Alzheimer's disease than other areas, a mechanism underlying the differential regional vulnerability to Alzheimer's disease remains to be elucidated. Using fluorodeoxyglucose and Pittsburgh compound B positron emission tomography imaging glucose metabolism and amyloid-β deposition, we tested whether and how life-long changes in glucose metabolism relate to amyloid-β deposition and Alzheimer's disease-related hypometabolism. Nine healthy young adults (age range: 20-30), 96 cognitively normal older adults (age range: 61-96), and 20 patients with Alzheimer's disease (age range: 50-90) were scanned using fluorodeoxyglucose and Pittsburgh compound B positron emission tomography.

Loss of functional connectivity is greater outside the default mode network in nonfamilial early-onset Alzheimer's disease variants.

The common and specific involvement of brain networks in clinical variants of Alzheimer's disease (AD) is not well understood. We performed task-free ("resting-state") functional imaging in 60 nonfamilial AD patients, including 20 early-onset AD (age at onset <65 years, amnestic/dysexecutive deficits), 24 logopenic aphasia (language deficits), and 16 posterior cortical atrophy patients (visual deficits), as well as 60 healthy controls. Seed-based connectivity analyses were conducted to assess differences between groups in 3 default mode network (DMN) components (anterior, posterior, and ventral) and 4 additional non-DMN networks: left and right executive-control, language, and higher visual networks.

Existing Pittsburgh Compound-B positron emission tomography thresholds are too high: statistical and pathological evaluation.

Amyloid-β, a hallmark of Alzheimer's disease, begins accumulating up to two decades before the onset of dementia, and can be detected in vivo applying amyloid-β positron emission tomography tracers such as carbon-11-labelled Pittsburgh compound-B. A variety of thresholds have been applied in the literature to define Pittsburgh compound-B positron emission tomography positivity, but the ability of these thresholds to detect early amyloid-β deposition is unknown, and validation studies comparing Pittsburgh compound-B thresholds to post-mortem amyloid burden are lacking. In this study we first derived thresholds for amyloid positron emission tomography positivity using Pittsburgh compound-B positron emission tomography in 154 cognitively normal older adults with four complementary approaches: (i) reference values from a young control group aged between 20 and 30 years; (ii) a Gaussian mixture model that assigned each subject a probability of being amyloid-β-positive or amyloid-β-negative based on Pittsburgh compound-B index uptake; (iii) a k-means cluster approach that clustered subjects into amyloid-β-positive or amyloid-β-negative based on Pittsburgh compound-B uptake in different brain regions (features); and (iv) an iterative voxel-based analysis that further explored the spatial pattern of early amyloid-β positron emission tomography signal.

Alzheimer Disease Biomarkers as Outcome Measures for Clinical Trials in MCI.

Background: The aim of this study was to compare the performance and power of the best-established diagnostic biological markers as outcome measures for clinical trials in patients with mild cognitive impairment (MCI).

Methods: Magnetic resonance imaging, F-18 fluorodeoxyglucose positron emission tomography markers, and Alzheimer's Disease Assessment Scale-cognitive subscale were compared in terms of effect size and statistical power over different follow-up periods in 2 MCI groups, selected from Alzheimer's Disease Neuroimaging Initiative data set based on cerebrospinal fluid (abnormal cerebrospinal fluid Aβ1-42 concentration-ABETA+) or magnetic resonance imaging evidence of Alzheimer disease (positivity to hippocampal atrophy-HIPPO+). Biomarkers progression was modeled through mixed effect models.

Effects of Beta-Amyloid on Resting State Functional Connectivity Within and Between Networks Reflect Known Patterns of Regional Vulnerability.

Beta-amyloid (Aβ) deposition is one of the hallmarks of Alzheimer's disease (AD). However, it is also present in some cognitively normal elderly adults and may represent a preclinical disease state. While AD patients exhibit disrupted functional connectivity (FC) both within and between resting-state networks, studies of preclinical cases have focused primarily on the default mode network (DMN).

Neural compensation in older people with brain amyloid-β deposition.

Recruitment of extra neural resources may allow people to maintain normal cognition despite amyloid-β (Aβ) plaques. Previous fMRI studies have reported such hyperactivation, but it is unclear whether increases represent compensation or aberrant overexcitation. We found that older adults with Aβ deposition had reduced deactivations in task-negative regions, but increased activation in task-positive regions related to more detailed memory encoding.

Vascular risk and Aβ interact to reduce cortical thickness in AD vulnerable brain regions.

Objective: The objective of this study was to define whether vascular risk factors interact with β-amyloid (Aβ) in producing changes in brain structure that could underlie the increased risk of Alzheimer disease (AD).

Methods: Sixty-six cognitively normal and mildly impaired older individuals with a wide range of vascular risk factors were included in this study. The presence of Aβ was assessed using [(11)C]Pittsburgh compound B-PET imaging, and cortical thickness was measured using 3-tesla MRI.

Parallel ICA of FDG-PET and PiB-PET in three conditions with underlying Alzheimer's pathology.

The relationships between clinical phenotype, β-amyloid (Aβ) deposition and neurodegeneration in Alzheimer's disease (AD) are incompletely understood yet have important ramifications for future therapy. The goal of this study was to utilize multimodality positron emission tomography (PET) data from a clinically heterogeneous population of patients with probable AD in order to: (1) identify spatial patterns of Aβ deposition measured by ((11)C)-labeled Pittsburgh Compound B (PiB-PET) and glucose metabolism measured by FDG-PET that correlate with specific clinical presentation and (2) explore associations between spatial patterns of Aβ deposition and glucose metabolism across the AD population. We included all patients meeting the criteria for probable AD (NIA-AA) who had undergone MRI, PiB and FDG-PET at our center (N = 46, mean age 63.

Cortical thickness mediates the effect of β-amyloid on episodic memory.

Objective: To investigate the associations among β-amyloid (Aβ), cortical thickness, and episodic memory in a cohort of cognitively normal to mildly impaired individuals at increased risk of vascular disease.

Methods: In 67 subjects specifically recruited to span a continuum of cognitive function and vascular risk, we measured brain Aβ deposition using [(11)C] Pittsburgh compound B-PET imaging and cortical thickness using MRI. Episodic memory was tested using a standardized composite score of verbal memory, and vascular risk was quantified using the Framingham Coronary Risk Profile index.

Associations between Alzheimer disease biomarkers, neurodegeneration, and cognition in cognitively normal older people.

Importance: 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.

Greater medial temporal hypometabolism and lower cortical amyloid burden in ApoE4-positive AD patients.

Background: Apolipoprotein E ε4 (ApoE4) has been associated with an increased risk of Alzheimer's disease (AD), amyloid deposition and hypometabolism. ApoE4 is less prevalent in non-amnestic AD variants suggesting a direct effect on the clinical phenotype. However, the impact of ApoE4 on amyloid burden and glucose metabolism across different clinical AD syndromes is not well understood.

Intrinsic connectivity networks in healthy subjects explain clinical variability in Alzheimer's disease.

Although previous studies have emphasized the vulnerability of the default mode network (DMN) in Alzheimer's disease (AD), little is known about the involvement of other functional networks and their relationship to clinical phenotype. To test whether clinicoanatomic heterogeneity in AD is driven by the involvement of specific networks, network connectivity was assessed in healthy subjects by seeding regions commonly and specifically atrophied in three clinical AD variants: early-onset AD (age at onset, <65 y; memory and executive deficits), logopenic variant primary progressive aphasia (language deficits), and posterior cortical atrophy (visuospatial deficits). Four-millimeter seed regions of interest were used to obtain intrinsic connectivity maps in 131 healthy controls (age, 65.

Effects of peripubertal gonadotropin-releasing hormone agonist on brain development in sheep--a magnetic resonance imaging study.

In many species sexual dimorphisms in brain structures and functions have been documented. In ovine model, we have previously demonstrated that peri-pubertal pharmacological blockade of gonadotropin releasing hormone (GnRH) action increased sex-differences of executive emotional behavior. The structural substrate of this behavioral alteration however is unknown.

Is verbal episodic memory in elderly with amyloid deposits preserved through altered neuronal function?

A potential mechanism that enables intellectual preservation in cognitively normal elderly that harbor beta-amyloid (Aβ) pathology is heightened cerebral glucose metabolism. To investigate cross-sectional inter-relationships between Aβ, glucose metabolism, and cognition, 81 subjects (mean age: 75 ± 7 years) underwent [(11)C]Pittsburgh Compound-B and [(18)F]fluorodeoxyglucose positron emission tomography scans and neuropsychological testing. They were divided into low-Aβ (n = 53), intermediate-Aβ (n = 13) and high-Aβ (n = 15) groups as defined by their global cortical [(11)C]PIB retention.

Alzheimer's disease neurodegenerative biomarkers are associated with decreased cognitive function but not β-amyloid in cognitively normal older individuals.

β-Amyloid (Aβ) plaque deposition and neurodegeneration within temporoparietal and hippocampal regions may indicate increased risk of Alzheimer's disease (AD). This study examined relationships between AD biomarkers of Aβ and neurodegeneration as well as cognitive performance in cognitively normal older individuals. Aβ burden was quantified in 72 normal older human subjects from the Berkeley Aging Cohort (BAC) using [(11)C] Pittsburgh compound B (PIB) positron emission tomography.

The aging brain and cognition: contribution of vascular injury and aβ to mild cognitive dysfunction.

Importance: β-Amyloid (Aβ) deposition and vascular brain injury (VBI) frequently co-occur and are both associated with cognitive decline in aging. Determining whether a direct relationship exists between them has been challenging. We sought to understand VBI's influence on cognition and clinical impairment, separate from and in conjunction with pathologic changes associated with Alzheimer disease (AD).

Association of gray matter atrophy with age, β-amyloid, and cognition in aging.

Both cognitive aging and β-amyloid (Aβ) deposition, a pathological hallmark of Alzheimer's disease, are associated with structural and cognitive changes in cognitively normal older people. To examine independent effects of age and Aβ deposition on cognition and brain structure in aging, 83 cognitively normal older adults underwent structural magnetic resonance imaging scans and neuropsychological tests and were classified as negative (PIB-) or positive (PIB+) for Aβ deposition using the radiotracer Pittsburgh compound B (PIB). Weighted composite discriminant scores represented subjects' cognition.

Diverging patterns of amyloid deposition and hypometabolism in clinical variants of probable Alzheimer's disease.

The factors driving clinical heterogeneity in Alzheimer's disease are not well understood. This study assessed the relationship between amyloid deposition, glucose metabolism and clinical phenotype in Alzheimer's disease, and investigated how these relate to the involvement of functional networks. The study included 17 patients with early-onset Alzheimer's disease (age at onset <65 years), 12 patients with logopenic variant primary progressive aphasia and 13 patients with posterior cortical atrophy [whole Alzheimer's disease group: age = 61.

Covarying alterations in Aβ deposition, glucose metabolism, and gray matter volume in cognitively normal elderly.

β-Amyloid (Aβ), a feature of Alzheimer's disease (AD) pathology, may precede reduced glucose metabolism and gray matter (GM) volume and cognitive decline in patients with AD. Accumulation of Aβ, however, has been also reported in cognitively intact older people, although it remains unresolved whether and how Aβ deposition, glucose metabolism, and GM volume relate to one another in cognitively normal elderly. Fifty-two cognitively normal older adults underwent Pittsburgh Compound B-positron emission tomography (PIB-PET), [(18)F]fluorodeoxyglucose-PET, and structural magnetic resonance imaging to measure whole-brain amyloid deposition, glucose metabolism, and GM volume, respectively.

Striatal dopamine influences the default mode network to affect shifting between object features.

Cognitive flexibility or the ability to change behavior in response to external cues is conceptualized as two processes: one for shifting between perceptual features of objects and another for shifting between the abstract rules governing the selection of these objects. Object and rule shifts are believed to engage distinct anatomical structures and functional processes. Dopamine activity has been associated with cognitive flexibility, but patients with dopaminergic deficits are not impaired on all tasks assessing cognitive flexibility, suggesting that dopamine may have different roles in the shifting of objects and rules.

Effects of age and β-amyloid on cognitive changes in normal elderly people.

Age-related decline is common in multiple cognitive domains. β-amyloid (Aβ) deposition, a pathological hallmark of Alzheimer's disease, is also associated with cognitive changes in many older people. In this study, we examined a wide range of cognitive function in order to differentiate the effect of age and Aβ on cognition during aging.

Summary metrics to assess Alzheimer disease-related hypometabolic pattern with 18F-FDG PET: head-to-head comparison.

Unlabelled: In the recently revised diagnostic criteria for Alzheimer disease (AD), the National Institute on Aging and Alzheimer Association suggested that confidence in diagnosing dementia due to AD and mild cognitive impairment (MCI) due to AD could be improved by the use of certain biomarkers, such as (18)F-FDG PET evidence of hypometabolism in AD-affected brain regions. Three groups have developed automated data analysis techniques to characterize the AD-related pattern of hypometabolism in a single measurement. In this study, we sought to directly compare the ability of these three (18)F-FDG PET data analysis techniques--the PMOD Alzheimer discrimination analysis tool, the hypometabolic convergence index, and a set of meta-analytically derived regions of interest reflecting AD hypometabolism pattern (metaROI)--to distinguish moderate or mild AD dementia patients and MCI patients who subsequently converted to AD dementia from cognitively normal older adults.

Subjective cognition and amyloid deposition imaging: a Pittsburgh Compound B positron emission tomography study in normal elderly individuals.

Objective: To study the relationship between subjective cognition and the neuropathological hallmark of Alzheimer disease (AD), amyloid-β (Aβ) deposition, using carbon 11-labeled Pittsburgh Compound B (PiB) positron emission tomography in normal elderly individuals.

Design: Cross-sectional analysis.

Subjects: Forty-eight cognitively normal elderly subjects (11 with high PiB uptake and 28 with low PiB uptake) were included.

Cerebrovascular disease, β-amyloid, and cognition in aging.

The present study evaluated cerebrovascular disease (CVD), β-amyloid (Aβ), and cognition in clinically normal elderly adults. Fifty-four participants underwent magnetic resonance imaging (MRI), Pittsburgh compound B (PIB)-positron emission tomography (PET) imaging, and neuropsychological evaluation. High white matter hyperintensity burden and/or presence of infarct defined CVD status (CVD-: n = 27; CVD+: n = 27).

Aβ Deposition in aging is associated with increases in brain activation during successful memory encoding.

To investigate early effects of beta-amyloid (Aβ) on neuronal function, elderly normal controls (NCs, age range 58-97) were scanned with Pittsburgh Compound-B (PIB) positron emission tomography (a measure of Aβ) as well as functional magnetic resonance imaging (a measure of brain activation) while performing an episodic memory-encoding task of natural scenes (also performed by young NCs; age range 18-30). Relationships between Aβ and activation were assessed across task-positive (regions that activate for subsequently remembered vs. forgotten scenes) and task-negative regions (regions that deactivate for subsequently remembered vs.