n-(2-methoxybenzyl)-n-(4-phenoxypyridin-3-yl)acetamide and Alzheimer-Disease

Deficits in neuronal function and synaptic plasticity in Alzheimer's disease (AD) are believed to be linked to microglial activation. A hallmark of reactive microglia is the upregulation of mitochondrial translocator protein (TSPO) expression. Positron emission tomography (PET) is a nuclear imaging technique that measures the distribution of trace doses of radiolabeled compounds in the body over time. PET imaging using the 2nd generation TSPO tracer [

Topics: Acetamides; Alzheimer Disease; Animals; Brain; Carbon Radioisotopes; Case-Control Studies; Female; Humans; Male; Mice; Mice, Transgenic; Microglia; Middle Aged; Positron-Emission Tomography; Pyridines; Receptors, GABA

Topics: Acetamides; Aged; Alzheimer Disease; Astrocytoma; Brain Neoplasms; Carbon Radioisotopes; Female; Humans; Positron-Emission Tomography; Pyridines; Receptors, GABA

This longitudinal study sought to determine whether the 18 kDa translocator protein (TSPO), a marker of neuroinflammation, increases over time in Alzheimer's disease. Positron emission tomography imaging with the TSPO radioligand (11)C-PBR28 was performed at baseline and after a median follow-up of 2.7 years in 14 amyloid-positive patients and 8 amyloid-negative controls. Patients had a greater increase in TSPO binding than controls in inferior parietal lobule, precuneus, occipital cortex, hippocampus, entorhinal cortex, and combined middle and inferior temporal cortex. TSPO binding in temporoparietal regions increased from 3.9% to 6.3% per annum in patients, but ranged from -0.5% to 1% per annum in controls. The change in TSPO binding correlated with cognitive worsening on clinical dementia rating scale-sum of boxes and reduced cortical volume. The annual rate of increased TSPO binding in temporoparietal regions was about 5-fold higher in patients with clinical progression (n = 9) compared with those who did not progress (n = 5). TSPO may serve as a biomarker of Alzheimer's progression and response to anti-inflammatory therapies.

Topics: Acetamides; Aged; Alzheimer Disease; Biomarkers; Brain; Carbon Radioisotopes; Disease Progression; Female; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Middle Aged; Neuroimaging; Positron-Emission Tomography; Protein Binding; Pyridines; Radiopharmaceuticals; Receptors, GABA

Brain amyloid deposition is thought to be a seminal event in Alzheimer's disease. To identify genes influencing Alzheimer's disease pathogenesis, we performed a genome-wide association study of longitudinal change in brain amyloid burden measured by (18)F-florbetapir PET. A novel association with higher rates of amyloid accumulation independent from APOE (apolipoprotein E) ε4 status was identified in IL1RAP (interleukin-1 receptor accessory protein; rs12053868-G; P = 1.38 × 10(-9)) and was validated by deep sequencing. IL1RAP rs12053868-G carriers were more likely to progress from mild cognitive impairment to Alzheimer's disease and exhibited greater longitudinal temporal cortex atrophy on MRI. In independent cohorts rs12053868-G was associated with accelerated cognitive decline and lower cortical (11)C-PBR28 PET signal, a marker of microglial activation. These results suggest a crucial role of activated microglia in limiting amyloid accumulation and nominate the IL-1/IL1RAP pathway as a potential target for modulating this process.

Topics: Acetamides; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid; Aniline Compounds; Apolipoprotein E4; Cerebral Cortex; Ethylene Glycols; Female; Genetic Association Studies; Genotype; Humans; Interleukin-1 Receptor Accessory Protein; Longitudinal Studies; Male; Polymorphism, Single Nucleotide; Positron-Emission Tomography; Pyridines

Second-generation radioligands for translocator protein (TSPO), an inflammation marker, are confounded by the codominant rs6971 polymorphism that affects binding affinity. The resulting three groups are homozygous for high-affinity state (HH), homozygous for low-affinity state (LL), or heterozygous (HL). We tested if in vitro binding to leukocytes distinguished TSPO genotypes and if genotype could affect clinical studies using the TSPO radioligand [(11)C]PBR28. In vitro binding to leukocytes and [(11)C]PBR28 brain imaging were performed in 27 human subjects with known TSPO genotype. Specific [(3)H]PBR28 binding was measured in prefrontal cortex of 45 schizophrenia patients and 47 controls. Leukocyte binding to PBR28 predicted genotype in all subjects. Brain uptake was ∼40% higher in HH than HL subjects. Specific [(3)H]PBR28 binding in LL controls was negligible, while HH controls had ∼80% higher binding than HL controls. After excluding LL subjects, specific binding was 16% greater in schizophrenia patients than controls. This difference was insignificant by itself (P=0.085), but was significant after correcting for TSPO genotype (P=0.011). Our results show that TSPO genotype influences PBR28 binding in vitro and in vivo. Correcting for this genotype increased statistical power in our postmortem study and is recommended for in vivo positron emission tomography studies.

Topics: Acetamides; Alzheimer Disease; Biomarkers; Brain; Carbon Radioisotopes; Case-Control Studies; Heterozygote; Homozygote; Humans; In Vitro Techniques; Leukocytes; Polymorphism, Single Nucleotide; Positron-Emission Tomography; Protein Binding; Pyridines; Radioligand Assay; Radiopharmaceuticals; Receptors, GABA; Schizophrenia; Tritium