Increased Binding of Peripheral Benzodiazepine Receptor in Alzheimer's Disease Measured by Positron Emission Tomography with [C-11]DAA1106

Clinical Neuroimaging Section, Department of Molecular Neuroimaging, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
Biological psychiatry (Impact Factor: 10.26). 06/2008; 64(10):835-41. DOI: 10.1016/j.biopsych.2008.04.021
Source: PubMed


Peripheral benzodiazepine receptor (PBR) in the brain of Alzheimer's disease (AD) patients has been discussed in relation to the role of gliosis in AD. The PBR was shown to have the ability to reflect activated glial cells, including microglia. The role of activated microglia in AD is an important topic in the pathophysiology of AD. The aim of this study was to quantify PBR in AD brain with a new high-sensitive PBR ligand, [(11)C]DAA1106.
Positron emission tomography (PET) scans with [(11)C]DAA1106, a potent and selective ligand for PBR, were performed on 10 patients with AD and 10 age-matched control subjects. All patients had mild to moderate dementia. Duration of illness was 1-3 years at the time of the scans. The PBR binding in the regions of interest was quantified by binding potential (BP) obtained from compartmental model analysis with plasma input function.
Mean BP was increased in the brain of AD patients compared with control subjects in all measured regions. Statistical significance reached across many of the regions examined, including dorsal and medial prefrontal cortex, lateral temporal cortex, parietal cortex, occipital cortex, anterior cingulate cortex, striatum, and cerebellum.
The broad increase of PBR binding measured with [(11)C]DAA1106 in the brain of AD patients suggests a widespread existence of cellular reactions with PBR in relatively early-stage AD.

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Available from: Fumihiko Yasuno, Jul 23, 2014
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    • "For example, this method was used recently to demonstrate widespread neuroinflammation in patients with mild cognitive impairment and Alzheimer's Disease (AD) compared to agematched controls [11]. Similarly, a prior study found increased [ 11 C] DAA1106 binding in participants with AD compared with control subjects across many regions, including dorsal and medial prefrontal cortex, lateral temporal cortex, parietal cortex, occipital cortex, anterior cingulate cortex, striatum, and cerebellum [12]. [(3)H] DAA1106 binding was also found to be elevated in a rat model of traumatic brain injury [13] [14]. "
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    ABSTRACT: Introduction: When microglia become activated (an integral part of neuroinflammation), cellular morphology changes and expression of translocator protein (TSPO) 18 kDa is increased. Over the past several years, [(11)C]DAA1106 has emerged as a reliable radiotracer for labeling TSPO with high affinity during positron emission tomography (PET) scanning. While [(11)C]DAA1106 PET scanning has been used in several research studies, a radiation dosimetry study of this radiotracer in humans has not yet been published. Methods: Twelve healthy participants underwent full body dynamic [(11)C]DAA1106 PET scanning, with 8 sequential whole body scans (approximately 12 bed positions each), following a single injection. Regions of interest were drawn manually, and time activity curves (TACs) were obtained for 15 organs. OLINDA/EXM 1.1 was used to compute radiation absorbed doses to the target organs, as well as effective dose (ED) and effective dose equivalent (EDE). Results: The ED and EDE were 4.06 ± 0.58 μSv/MBq and 5.89 ± 0.83 μSv/MBq, respectively. The highest absorbed doses were to the heart wall, kidney, liver, pancreas, and spleen. TACs revealed that peak dose rates are during the first scan (at 6 min) for all organs other than the urinary bladder wall, which had its peak dose rate during the fourth scan (at 30 min). Conclusions: The recently developed radiotracer [(11)C]DAA1106 has its EDE and target-organ absorbed dose such that, for a single administration, its radiation dosimetry is well within the U.S. FDA guidelines for basic research studies in adults. This dose level implies that the dosimetry for multiple [(11)C]DAA1106 scans within a given year also falls within FDA guidelines, and this favorable property makes this radiotracer suitable for examining microglial activation repeatedly over time, which may in the future be useful for longitudinal tracking of disease progression and monitoring of therapy response in conditions marked by neuroinflammation (e.g., head trauma and multiple sclerosis).
    Nuclear Medicine and Biology 08/2014; 41(10). DOI:10.1016/j.nucmedbio.2014.07.004 · 2.41 Impact Factor
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    • "Among second generation TSPO radioligands, increased binding of [11C]DAA1106 has been observed in AD, as compared to controls, though no correlation was found with respect to disease severity [75]. In a follow-up study among patients with MCI, the increased binding was associated with progression to AD over a 5-year follow-up period [39]. "
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    ABSTRACT: Alzheimer's disease (AD) has been reconceptualized as a dynamic pathophysiological process, where the accumulation of amyloid-beta (Abeta) is thought to trigger a cascade of neurodegenerative events resulting in cognitive impairment and, eventually, dementia. In addition to Abeta pathology, various lines of research have implicated neuroinflammation as an important participant in AD pathophysiology. Currently, neuroinflammation can be measured in vivo using positron emission tomography (PET) with ligands targeting diverse biological processes such as microglial activation, reactive astrocytes and phospholipase A2 activity. In terms of therapeutic strategies, despite a strong rationale and epidemiological studies suggesting that the use of non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the prevalence of AD, clinical trials conducted to date have proven inconclusive. In this respect, it has been hypothesized that NSAIDs may only prove protective if administered early on in the disease course, prior to the accumulation of significant AD pathology. In order to test various hypotheses pertaining to the exact role of neuroinflammation in AD, studies in asymptomatic carriers of mutations deterministic for early-onset familial AD may prove of use. In this respect, PET ligands for neuroinflammation may act as surrogate markers of disease progression, allowing for the development of more integrative models of AD, as well as for the measuring of target engagement in the context of clinical trials using NSAIDs. In this review, we address the biological basis of neuroinflammatory changes in AD, underscore therapeutic strategies using anti-inflammatory compounds, and shed light on the possibility of tracking neuroinflammation in vivo using PET imaging ligands.
    Journal of Neuroinflammation 07/2014; 11(1):120. DOI:10.1186/1742-2094-11-120 · 5.41 Impact Factor
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    • "Several second generation TSPO radioligands have been developed (Chauveau et al., 2008). Of these, only 11 C-DAA1106 has been used to detect increased TSPO in Alzheimer's disease (Yasuno et al., 2008). In that study, patients with Alzheimer's disease had greater 11 C-DAA1106 binding than control subjects in several brain regions, including regions typically less affected by the disease, such as cerebellum and occipital cortex. "

    Alzheimer's and Dementia 07/2013; 9(4):P337. DOI:10.1016/j.jalz.2013.04.196 · 12.41 Impact Factor
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