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

ABSTRACT 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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Available from: Raymond Scott Turner, Sep 27, 2015
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    • "C]N-acetyl-N-(2-methoxybenzyl)-2-phenoxy-5-pyridin- amine). 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). Amyloid plaques have been identified as a major source of neuroinflammation in AD. "
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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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