PET of Brain Amyloid and Tau in Mild Cognitive Impairment

Department of Psychiatry and Biobehavioural Sciences, University of California, Los Angeles, Los Ángeles, California, United States
New England Journal of Medicine (Impact Factor: 55.87). 12/2006; 355(25):2652-63. DOI: 10.1056/NEJMoa054625
Source: PubMed


Amyloid senile plaques and tau neurofibrillary tangles are neuropathological hallmarks of Alzheimer's disease that accumulate in the cortical regions of the brain in persons with mild cognitive impairment who are at risk for Alzheimer's disease. Noninvasive methods to detect these abnormal proteins are potentially useful in developing surrogate markers for drug discovery and diagnostics.
We enrolled 83 volunteers with self-reported memory problems who had undergone neurologic and psychiatric evaluation and positron-emission tomography (PET). On the basis of cognitive testing, 25 volunteers were classified as having Alzheimer's disease, 28 as having mild cognitive impairment, and 30 as having no cognitive impairment (healthy controls). PET was performed after injection of 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP), a molecule that binds to plaques and tangles in vitro. All subjects also underwent 2-deoxy-2-[F-18]fluoro-D-glucose (FDG) PET, and 72 underwent magnetic resonance imaging (MRI).
Global values for FDDNP-PET binding (average of the values for the temporal, parietal, posterior cingulate, and frontal regions) were lower in the control group than in the group with mild cognitive impairment (P<0.001), and the values for binding in the group with mild cognitive impairment were lower than in the group with Alzheimer's disease (P<0.001). FDDNP-PET binding differentiated among the diagnostic groups better than did metabolism on FDG-PET or volume on MRI.
FDDNP-PET scanning can differentiate persons with mild cognitive impairment from those with Alzheimer's disease and those with no cognitive impairment. This technique is potentially useful as a noninvasive method to determine regional cerebral patterns of amyloid plaques and tau neurofibrillary tangles.

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    • "The identification of suitable individuals with elevated brain amyloid burden poses a great challenge in terms of feasibility and cost. To date, the advancement of molecular imaging tracers that bind to amyloid, such as Pittsburgh Compound B (PiB), offers a noninvasive in vivo method to detect and quantify brain amyloid deposition [3] [4]. However, this approach for pre-symptomatic detection is economically challenging for routine use given the current cost [5]. "
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    ABSTRACT: Background: Detecting participants who are positive for amyloid-β (Aβ) pathology is germane in designing prevention trials by enriching for those cases that are more likely to be amyloid positive. Existing brain amyloid measurement techniques, such as the Pittsburgh Compound B-positron emission tomography and cerebrospinal fluid, are not reasonable first-line approaches limited by either feasibility or cost. Objective: We aimed to identify simple and cost-effective rules that can predict brain Aβ level by integrating both neuropsychological measurements and blood-based markers. Method: Several decision tree models were built for extracting the predictive rules based on the Alzheimer's Disease Neuroimaging Initiative cohort. Results: We successfully extracted predictive rules of Aβ level. For cognitive function variables, cases above the 45th percentile in total cognitive score (TOTALMOD), above the 52nd percentile of delayed word recall, and above the 70th percentile in orientation resulted in a group that was highly enriched for amyloid negative cases. Conversely scoring below the 15th percentile of TOTALMOD resulted in a group highly enriched for amyloid positive cases. For blood protein markers, scoring below the 57th percentile for apolipoprotein E (ApoE) levels (irrespective of genotype) enriched two fold for the risk of being amyloid positive. In the high ApoE cases, scoring above the 60th percentile for transthyretin resulted in a group that was >90% amyloid negative. A third decision tree using both cognitive and blood-marker data slightly improved the classification of cases. Conclusion: Our study demonstrated that the integration of the neuropsychological measurements and blood-based markers significantly improved prediction accuracy. The prediction model has led to several simple rules, which have a great potential of being naturally translated into clinical settings such as enrichment screening for AD prevention trials of anti-amyloid treatments.
    Journal of Alzheimer's disease: JAD 08/2014; 43(4). DOI:10.3233/JAD-140705 · 4.15 Impact Factor
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    • "The establishment of aMCI biomarkers would be of benefit to clinicians as the biomarkers could be used as objective diagnostic tools, thus allowing early or pre-symptomatic identification of AD, aiding treatment decisions, monitoring disease progress, and providing opportunities for prevention by population screening (Henry et al., 2012). The methods used to search for biomarkers of MCI include neuroimaging techniques (Small et al., 2006; Hämäläinen et al., 2007), cerebrospinal fluid analysis (Perneczky et al., 2011), genetic analysis (Zhang et al., 2012) and electroencephalography (EEG), both quantitative EEG (see Jackson and Snyder, 2008) and event-related potentials (ERPs; see Jackson and Snyder, 2008 and Vecchio and Määttä, 2011). The use of ERP technique in the search for aMCI biomarkers is founded on three essential characteristics designated as ideal (see Hampel et al., 2010): it is non-invasive, simple to measure and inexpensive. "
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    ABSTRACT: It has been suggested that changes in some event-related potential (ERP) parameters associated with controlled processing of stimuli could be used as biomarkers of amnestic mild cognitive impairment (aMCI). However, data regarding the suitability of ERP components associated with automatic and involuntary processing of stimuli for this purpose are not conclusive. In the present study, we studied the Mismatch Negativity (MMN) component, a correlate of the automatic detection of changes in the acoustic environment, in healthy adults and adults with aMCI (age range: 50-87 years). An auditory-visual attention-distraction task, in two evaluations separated by an interval of between 18 and 24 months, was used. In both evaluations, the MMN amplitude was significantly smaller in the aMCI adults than in the control adults. In the first evaluation, such differences were observed for the subgroup of adults between 50 and 64 years of age, but not for the subgroup of 65 years and over. In the aMCI adults, the MMN amplitude was significantly smaller in the second evaluation than in the first evaluation, but no significant changes were observed in the control adult group. The MMN amplitude was found to be a sensitive and specific biomarker of aMCI, in both the first and second evaluation.
    Frontiers in Aging Neuroscience 12/2013; 5:79. DOI:10.3389/fnagi.2013.00079 · 4.00 Impact Factor
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    • "[18F]FDDNP (2-(1-{6-[18]fluoroethyl}(methyl)amino)-2-naphthyl)ethylidene)malonononitrile) binds both amyloid-β plaques and neurofibrillary tangles, and it has therefore been suggested that it could be sensitive to pathological changes early in the disease progress [8]. However, when compared to other amyloid radioligands, [18F]FDDNP has a ninefold lower specific binding signal in AD patients, which might explain why recent longitudinal studies have shown different results [9]. "
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    ABSTRACT: Purpose The aim of this study was to evaluate AZD2995 side by side with AZD2184 as novel PET radioligands for imaging of amyloid-β in Alzheimer’s disease (AD). Methods In vitro binding of tritium-labelled AZD2995 and AZD2184 was studied and compared with that of the established amyloid-β PET radioligand PIB. Subsequently, a first-in-human in vivo PET study was performed using [11C]AZD2995 and [11C]AZD2184 in three healthy control subjects and seven AD patients. Results AZD2995, AZD2184 and PIB were found to share the same binding site to amyloid-β. [3H]AZD2995 had the highest signal-to-background ratio in brain tissue from patients with AD as well as in transgenic mice. However, [11C]AZD2184 had superior imaging properties in PET, as shown by larger effect sizes comparing binding potential values in cortical regions of AD patients and healthy controls. Nevertheless, probably due to a lower amount of nonspecific binding, the group separation of the distribution volume ratio values of [11C]AZD2995 was greater in areas with lower amyloid-β load, e.g. the hippocampus. Conclusion Both AZD2995 and AZD2184 detect amyloid-β with high affinity and specificity and also display a lower degree of nonspecific binding than that reported for PIB. Overall [11C]AZD2184 seems to be an amyloid-β radioligand with higher uptake and better group separation when compared to [11C]AZD2995. However, the very low nonspecific binding of [11C]AZD2995 makes this radioligand potentially interesting as a tool to study minute levels of amyloid-β. This sensitivity may be important in investigating, for example, early prodromal stages of AD or in the longitudinal study of a disease modifying therapy.
    European journal of nuclear medicine and molecular imaging 04/2013; 40(4). DOI:10.1007/s00259-012-2322-6 · 5.38 Impact Factor
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