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.
Abstract Since the introduction of amyloid imaging nearly 10 years ago, this technique has gained widespread use and acceptance. More recently, published reports have begun to appear in which amyloid ...imaging is used to detect the effects of antiamyloid therapies. This review will consider the issues involved in the use of amyloid imaging in the development and evaluation of drugs for the treatment of Alzheimer's disease. Current evidence regarding the postmortem correlates of in vivo amyloid imaging data are considered. The application of amyloid imaging to screening subjects for trials and use as an outcome measure is discussed in light of longitudinal changes in the in vivo amyloid signal. While the bulk of this review is directed at symptomatic patients with dementia, consideration is given to the use of amyloid imaging in nondemented subjects as well. Similarities and differences of cerebral amyloid assessment by amyloid imaging and cerebrospinal fluid (CSF) measurements are delineated and an agenda for further research to improve the applicability of amyloid positron emission tomography (PET) to clinical trials is proposed.
Alzheimer's disease (AD) is a progressive age-related neurodegenerative disease. At the time of clinical manifestation of dementia, significant irreversible brain damage is already present, rendering ...the diagnosis of AD at early stages of the disease an urgent prerequisite for therapeutic treatment to halt, or at least slow, disease progression. In this review, we discuss various neuroimaging measures that are proving to have potential value as biomarkers of AD pathology for the detection and prediction of AD before the onset of dementia. Recent studies that have identified AD-like structural and functional brain changes in elderly people who are cognitively within the normal range or who have mild cognitive impairment (MCI) are discussed. A dynamic sequence model of changes that occur in neuroimaging markers during the different disease stages is presented and the predictive value of multimodal neuroimaging for AD dementia is considered.
Objective
To examine region‐ and substrate‐specific autoradiographic and in vitro binding patterns of positron emission tomography tracer F‐18‐AV‐1451 (previously known as T807), tailored to allow in ...vivo detection of paired helical filament‐tau–containing lesions, and to determine whether there is off‐target binding to other amyloid/non‐amyloid proteins.
Methods
We applied F‐18‐AV‐1451 phosphor screen autoradiography, F‐18‐AV‐1451 nuclear emulsion autoradiography, and H‐3‐AV‐1451 in vitro binding assays to the study of postmortem samples from patients with a definite pathological diagnosis of Alzheimer disease, frontotemporal lobar degeneration–tau, frontotemporal lobar degeneration–transactive response DNA binding protein 43 (TDP‐43), progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies, multiple system atrophy, cerebral amyloid angiopathy and elderly controls free of pathology.
Results
Our data suggest that F‐18‐AV‐1451 strongly binds to tau lesions primarily made of paired helical filaments in Alzheimer brains (eg, intraneuronal and extraneuronal tangles and dystrophic neurites), but does not seem to bind to a significant extent to neuronal and glial inclusions mainly composed of straight tau filaments in non‐Alzheimer tauopathy brains or to lesions containing β‐amyloid, α‐synuclein, or TDP‐43. F‐18‐AV‐1451 off‐target binding to neuromelanin‐ and melanin‐containing cells and, to a lesser extent, to brain hemorrhagic lesions was identified.
Interpretation
Our data suggest that F‐18‐AV‐1451 holds promise as a surrogate marker for the detection of brain tau pathology in the form of tangles and paired helical filament‐tau–containing neurites in Alzheimer brains but also point to its relatively lower affinity for lesions primarily made of straight tau filaments in non‐Alzheimer tauopathy cases and to the existence of some F‐18‐AV‐1451 off‐target binding. These findings provide important insights for interpreting in vivo patterns of F‐18‐AV‐1451 retention. Ann Neurol 2015 Ann Neurol 2015;78:Ann Neurol 2015;78:679–696
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.
Alzheimer's disease (AD) and antecedent factors associated with AD were explored using amyloid imaging and unbiased measures of longitudinal atrophy in combination with reanalysis of previous ...metabolic and functional studies. In total, data from 764 participants were compared across five in vivo imaging methods. Convergence of effects was seen in posterior cortical regions, including posterior cingulate, retrosplenial, and lateral parietal cortex. These regions were active in default states in young adults and also showed amyloid deposition in older adults with AD. At early stages of AD progression, prominent atrophy and metabolic abnormalities emerged in these posterior cortical regions; atrophy in medial temporal regions was also observed. Event-related functional magnetic resonance imaging studies further revealed that these cortical regions are active during successful memory retrieval in young adults. One possibility is that lifetime cerebral metabolism associated with regionally specific default activity predisposes cortical regions to AD-related changes, including amyloid deposition, metabolic disruption, and atrophy. These cortical regions may be part of a network with the medial temporal lobe whose disruption contributes to memory impairment.
Brain imaging in Alzheimer disease Johnson, Keith A; Fox, Nick C; Sperling, Reisa A ...
Cold Spring Harbor perspectives in medicine,
04/2012, Volume:
2, Issue:
4
Journal Article
Peer reviewed
Open access
Imaging has played a variety of roles in the study of Alzheimer disease (AD) over the past four decades. Initially, computed tomography (CT) and then magnetic resonance imaging (MRI) were used ...diagnostically to rule out other causes of dementia. More recently, a variety of imaging modalities including structural and functional MRI and positron emission tomography (PET) studies of cerebral metabolism with fluoro-deoxy-d-glucose (FDG) and amyloid tracers such as Pittsburgh Compound-B (PiB) have shown characteristic changes in the brains of patients with AD, and in prodromal and even presymptomatic states that can help rule-in the AD pathophysiological process. No one imaging modality can serve all purposes as each have unique strengths and weaknesses. These modalities and their particular utilities are discussed in this article. The challenge for the future will be to combine imaging biomarkers to most efficiently facilitate diagnosis, disease staging, and, most importantly, development of effective disease-modifying therapies.
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.
The National Institute on Aging and the Alzheimer's Association charged a workgroup with the task of revising the 1984 criteria for Alzheimer's disease (AD) dementia. The workgroup sought to ensure ...that the revised criteria would be flexible enough to be used by both general healthcare providers without access to neuropsychological testing, advanced imaging, and cerebrospinal fluid measures, and specialized investigators involved in research or in clinical trial studies who would have these tools available. We present criteria for all-cause dementia and for AD dementia. We retained the general framework of probable AD dementia from the 1984 criteria. On the basis of the past 27 years of experience, we made several changes in the clinical criteria for the diagnosis. We also retained the term possible AD dementia, but redefined it in a manner more focused than before. Biomarker evidence was also integrated into the diagnostic formulations for probable and possible AD dementia for use in research settings. The core clinical criteria for AD dementia will continue to be the cornerstone of the diagnosis in clinical practice, but biomarker evidence is expected to enhance the pathophysiological specificity of the diagnosis of AD dementia. Much work lies ahead for validating the biomarker diagnosis of AD dementia.
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