Abstract
IntroductionMetabotropic glutamate receptors play a critical role in the pathogenesis of Alzheimer's disease due to their involvement in processes of memory formation, neuroplasticity, and synaptotoxity. The objective of the current study was to study mGluR5 availability measured by [11C]‐ABP688 (ABP) in patients with clinically diagnosed Alzheimer's dementia (AD).MethodsA bolus‐infusion protocol of [11C]‐ABP688 was applied in 9 subjects with AD and 10 cognitively healthy controls (Controls) to derive distribution volume estimates of mGluR5. Furthermore, we also estimated cerebral perfusion by averaging early frame signal of initial ABP bolus injection.ResultsSubjects with Alzheimer's dementia (mean age: 77.3/SD 5.7) were older than controls (mean age: 68.5/SD: 9.6) and scored lower on the MMSE (22.1/SD2.7 vs. 29.0/SD0.8). There were no overall differences in ABP signal. However, distribution volume ratio (DVR) for ABP was reduced in the bilateral hippocampus (AD: 1.34/SD: 0.40 vs. Control: 1.84/SD:0.31, p = .007) and the bilateral amygdala (AD:1.86/SD:0.26 vs. Control:2.33/SD:0.37 p = .006) in AD patients compared to controls.Estimate of cerebral blood flow was reduced in the bilateral hippocampus in AD (AD:0.75/SD:0.10 vs. Control:0.86/SD:0.09 p = .02).ConclusionOur findings demonstrate reduced mGluR5 binding in the hippocampus and amygdala in Alzheimer's dementia. Whether this is due to synaptic loss and/or consecutive reduction of potential binding sites or reflects disease inherent mechanisms remains to be elucidated in future studies.
Highlights
Metabotropic glutamate receptors play a critical role in the pathogenesis of Alzheimer's disease due to their involvement in processes of memory formation, neuroplasticity, and synaptotoxity
Distribution volume ratio (DVR) for ABP was reduced in the bilateral hippocampus (AD: 1.34/SD: 0.40 vs. Control: 1.84/SD:0.31, p = .007) and the bilateral amygdala (AD:1.86/SD:0.26 vs. Control:2.33/SD:0.37 p = .006) in Alzheimer's dementia (AD) patients compared to controls
Our findings demonstrate reduced metabotropic glutamate receptor 5 (mGluR5) binding in the hippocampus and amygdala in Alzheimer's dementia
Summary
The pathology of Alzheimer's disease can be divided in accumulation of aggregated proteins, extracellular beta-amyloid and intracellular phosphorylated tau, losses of synapses and neurons and reactive processes including activation of microglia, astrocytosis and regenerative processes of undetermined significance (Duyckaerts, Delatour, & Potier, 2009). Synaptic dysfunction and synaptic loss reportedly correlate strongly with cognitive decline (Scheff, Price, Schmitt, & Mufson, 2006; Terry et al, 1991) Both Abeta- and tau pathology contribute to synaptic dysfunction in Alzheimer's disease and exert a detrimental interaction at the synaptic level as reviewed by Forner, Baglietto-Vargas, Martini, Trujillo-Estrada, & LaFerla, 2017 (Forner et al, 2017). MGluR5 was necessary for cluster formation of Abeta-oligomers (Abetao) at the synaptic plasma membrane which in turn leads to altered redistribution of mGluR5 and aberrant Ca2+ mobilization (Renner et al, 2010) It mediated increases in intracellular Ca2+ and dendritic spine loss via complexes of prion protein and Abetao (Um et al, 2013). We expected reduced perfusion-related signal of ABP in subjects with Alzheimer's disease, as perfusion correlates with neuronal activity and cognitive performance, and is known to be reduced in Alzheimer's disease (Gietl et al, 2015; Rostomian, Madison, Rabinovici, & Jagust, 2011)
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