Association between cerebrospinal fluid biomarkers of neurodegeneration and PET measurements of synaptic density in Alzheimer's disease: Neuroimaging / multi‐modal comparisons. (7th December 2020) - Mecca, Adam P.
Abstract: Background: Studies using [ 11 C]UCB‐J–PET have shown significant reductions in synaptic glycoprotein 2A (SV2A) specific binding as a marker of synaptic density in early Alzheimer's disease (AD). The extent of these reductions indicates widespread neocortical synaptic loss that corroborates previous postmortem studies. The relationship of PET measures of synaptic density and cerebrospinal fluid (CSF) biomarkers may provide important information related to neuronal damage and synaptic health. Methods: SV2A binding was measured with [ 11 C]UCB‐J–PET in 21 participants with early AD (CDR=0.5‐1.0, PiB+) and 7 cognitively normal (CN) participants (CDR=0, PiB–). PET scans were performed on a HRRT from 60 or 90 min after a bolus injection of [ 11 C]UCB‐J. Binding potential non‐displaceable ( BP ND ) was calculated using SRTM2 and a centrum semiovale reference and converted to a distribution volume ratio ( DVR ) with a cerebellum reference. CSF biomarkers of AD, as well as synaptic and neuronal health were assayed, including Aβ42, Aβ40, total tau (t‐tau), phosphorylated tau (p‐tau), neurofilament light chain (NFL), growth‐associated protein 43 (GAP‐43), neurogranin (Ng), synaptosomal‐associated protein 25 (SNAP‐25), and synaptotagmin‐1 (SYT‐1). Results: Synaptic density was significantly lower in AD participants in the hippocampus, entorhinal cortex, lateral parietal cortex, lateral temporal cortex, and lateral occipital cortex. There were significant group differences in Aβ42, Aβ42/Aβ40, t‐tau, p‐tau, GAP‐43, Ng, SNAP‐25 short, and SNAP‐25 total. In the overall sample, only Aβ42 (r=0.40, P =0.03) and Aβ42/Aβ40 (r=0.48, P =0.01) had significant correlations with synaptic density in the hippocampus. Aβ42/Aβ40 (r=0.46), t‐tau (r=‐0.38), p‐tau (r=‐0.40), NFL (r=‐0.42), GAP‐43 (r=‐0.46), and SNAP‐25 total (r=‐0.49) were significantly correlated with synaptic density in a composite of commonly affected AD regions (P<0.05, Figure 1). Most CSF biomarkers were significantly correlated with synaptic density in the neocortex only (Figure 2). In addition, CSF Aβ42/Aβ40 and synaptic density were significantly correlated in regions of the medial temporal lobe (Figure 2). Conclusion: This study explores the relationship between synaptic density and CSF biomarkers of neuronal and synaptic health in AD. The spatial relationship between synaptic density reductions and CSF synaptic biomarkers may provide valuable information that will contribute to the understanding of AD and lead to novel treatments and therapeutic biomarkers.