In vivo radioligand binding to translocator protein correlates with severity of Alzheimer's disease

1 Molecular Imaging Branch, National Institute of Mental Health, Bethesda, MD, USA.
Brain (Impact Factor: 9.2). 06/2013; 136(7). DOI: 10.1093/brain/awt145
Source: PubMed


Neuroinflammation is a pathological hallmark of Alzheimer's disease, but its role in cognitive impairment and its course of development during the disease are largely unknown. To address these unknowns, we used positron emission tomography with (11)C-PBR28 to measure translocator protein 18 kDa (TSPO), a putative biomarker for inflammation. Patients with Alzheimer's disease, patients with mild cognitive impairment and older control subjects were also scanned with (11)C-Pittsburgh Compound B to measure amyloid burden. Twenty-nine amyloid-positive patients (19 Alzheimer's, 10 mild cognitive impairment) and 13 amyloid-negative control subjects were studied. The primary goal of this study was to determine whether TSPO binding is elevated in patients with Alzheimer's disease, and the secondary goal was to determine whether TSPO binding correlates with neuropsychological measures, grey matter volume, (11)C-Pittsburgh Compound B binding, or age of onset. Patients with Alzheimer's disease, but not those with mild cognitive impairment, had greater (11)C-PBR28 binding in cortical brain regions than controls. The largest differences were seen in the parietal and temporal cortices, with no difference in subcortical regions or cerebellum. (11)C-PBR28 binding inversely correlated with performance on Folstein Mini-Mental State Examination, Clinical Dementia Rating Scale Sum of Boxes, Logical Memory Immediate (Wechsler Memory Scale Third Edition), Trail Making part B and Block Design (Wechsler Adult Intelligence Scale Third Edition) tasks, with the largest correlations observed in the inferior parietal lobule. (11)C-PBR28 binding also inversely correlated with grey matter volume. Early-onset (<65 years) patients had greater (11)C-PBR28 binding than late-onset patients, and in parietal cortex and striatum (11)C-PBR28 binding correlated with lower age of onset. Partial volume corrected and uncorrected results were generally in agreement; however, the correlation between (11)C-PBR28 and (11)C-Pittsburgh Compound B binding was seen only after partial volume correction. The results suggest that neuroinflammation, indicated by increased (11)C-PBR28 binding to TSPO, occurs after conversion of mild cognitive impairment to Alzheimer's disease and worsens with disease progression. Greater inflammation may contribute to the precipitous disease course typically seen in early-onset patients. (11)C-PBR28 may be useful in longitudinal studies to mark the conversion from mild cognitive impairment or to assess response to experimental treatments of Alzheimer's disease.

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    • "However, as pathological studies [41] , as well as previous PET studies [37,38], show microglial activation in MCI patients, it is more likely that [ 11 C]PBR28 is not sensitive enough to detect a signal in MCI [40]. In another PET study using [ 11 C] PBR28 in AD patients (n = 25), MCI patients (n = 11) and healthy volunteers (n = 21), all genotyped [42], V T , calculated using the two-tissue compartment model (2TCM) with arterial input function, was compared with SUVr using cerebellum as pseudo-reference region (region in which TSPO is expressed, but the expression should not differ between groups [40] ). Differences in V T values were not observed between groups, but after correcting for the free fraction in plasma (f P ), AD patients showed higher V T /f P values in entorhinal and combined middle and inferior temporal cortices than both MCI patients and controls [42]. "
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    ABSTRACT: Neuroinflammation is thought to play a pivotal role in many diseases affecting the brain, including Alzheimer's disease, multiple sclerosis and stroke. Neuroinflammation is characterised predominantly by microglial activation, which can be visualised using positron emission tomography (PET). Traditionally, translocator protein 18 kDa (TSPO) is the target for imaging of neuroinflammation using PET. In this review, recent preclinical and clinical research using PET in Alzheimer's disease, multiple sclerosis and stroke is summarised. In addition, new molecular targets for imaging of neuroinflammation, such as monoamine oxidases, adenosine receptors and cannabinoid receptor type 2, are discussed. This article is part of a Special Issue entitled: Neuro Inflammation edited by Helga E. de Vries and Markus Schwaninger.
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    • "Activated microglia can be visualized by protein markers such as ionized calcium binding adaptor molecule 1 (Iba1) and translocator protein 18 kDa (TSPO) (Martin et al., 2010). In one key study, patients with AD, patients with mild cognitive impairment and older control subjects were scanned with the TSPO ligand (11)C-PBR28 ([methyl-(11)C]N-acetyl-N-(2-methoxybenzyl)-2- phenoxy-5-pyridinamine). Patients with AD had greater (11)C-PBR28 binding in cortical brain regions than controls, and (11)C-PBR28 binding inversely correlated with the patient's performance on a variety of neuropsychological tests (Kreisl et al., 2013). "
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    ABSTRACT: Alzheimer’s disease is a progressive neurodegenerative disorder, characterized by deposition of amyloid beta, neurofibrillary tangles, astrogliosis and microgliosis, leading to neuronal dysfunction and loss in the brain. Current treatments for Alzheimer’s disease primarily focus on enhancement of cholinergic transmission. However, these treatments are only symptomatic, and no disease-modifying drug is available for Alzheimer’s disease patients. This review will provide an overview of the proven antioxidant, anti-inflammatory, anti-amyloidogenic, neuroprotective, and cognition-enhancing effects of curcumin and apigenin and discuss the potential of these compounds for Alzheimer’s disease prevention and treatment. We suggest that these compounds might delay the onset of Alzheimer’s disease or slow down its progression, and they should enter clinical trials as soon as possible. © 2015, Editorial Board of Neural Regeneration Research. All rights reserved.
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    • "This, in turn, leads to loss of NMDAR density and loss of NMDAR expressing cells [27] in these regions, followed by secondary neuroinflammation in response to neuronal loss and disease progression. This model is supported by the correlation between regional neuroinflammation, but not plaque load, and cognitive abilities [7,21]; the decreased risk of AD in users of non steroidal anti-inflammatory agents coupled with the lack of efficacy of the same drugs in symptomatic AD [28,29], evidence of neuroinflammation in subjects with mild cognitive impairment who later converted to dementia [30] and the efficacy of memantine, a low-affinity non-competitive NMDAR antagonist which protects physiological synaptic transmission through NMDAR, in moderate to severe AD [31]. Furthermore, the close association between the region-specific decrease in NMDAR density and the progression of definite AD supports the use of positron-emitting NMDAR antagonists such as [11C]CNS5161 [32,33] in the diagnosis and staging of AD in vivo. "
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    ABSTRACT: Early Alzheimer's disease (AD) is characterized by memory loss and hippocampal atrophy with relative sparing of basal ganglia. Activation of glutamate NMDA receptors in the hippocampus is an important step in memory formation. We measured the density of NMDA receptors in samples of hippocampus, entorhinal cortex and basal ganglia obtained from subjects who died with pathologically confirmed AD and age- and sex- matched non-demented controls. We found significant decreases in NMDA receptor density in the hippocampus and entorhinal cortex but not in the basal ganglia. Loss of NMDA receptors was significantly correlated with neuropathological progression as assessed by Braak staging postmortem. The same samples were probed for neuroinflammation by measuring the density and gene expression of translocator protein 18kDA (TSPO), an established marker of microglial activation. Unlike NMDA receptor loss, increased densities of TSPO were found in all of the brain regions sampled. However hippocampal, but not striatal TSPO density and gene expression were inversely correlated with NMDA receptor density and positively correlated with Braak stage, suggesting NMDA receptors exacerbate neuroniflammatory damage. The high correlation between hippocampal NMDA receptor loss and disease progression supports the use of non invasive imaging with NMDA receptor tracers and positron emission tomography as a superior method for diagnosis, staging and treatment monitoring of AD in vivo.
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