Cerebrospinal fluid and brain PET measures of synaptic density glycoprotein 2A: Biomarkers of synaptic density in Alzheimer’s disease

Abstract

AbstractBackgroundSynaptic loss is linked with Alzheimer’s disease (AD) progression and provides a novel target for exploration with fluid and imaging biomarkers. Studies using [11C]UCB‐J–PET have shown significant reductions in synaptic glycoprotein 2A (SV2A) specific binding as a marker of synaptic density in early AD. The extent of these reductions indicates widespread neocortical synaptic loss that corroborates previous postmortem studies. This study examined the association between a SV2A measured with brain [11C]UCB‐J–PET and cerebrospinal fluid (CSF) levels of SV2A.MethodUsing [11C]UCB‐J binding to SV2A, synaptic density was measured 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 after a bolus injection of [11C]UCB‐J. Synaptic density was calculated as the distribution volume ratio (DVR) using SRTM2 with a cerebellum reference region. CSF SV2A was measured by an in‐house ELISA method.ResultAs previously demonstrated, synaptic density measured with SV2A PET was significantly lower in AD participants in the hippocampus, entorhinal cortex, lateral parietal cortex, lateral temporal cortex, and lateral occipital cortex. CSF SV2A was also reduced in participants with AD (762 ± 148) pg/mL) compared to CN participants (935 ± 134 pg/mL, P = 0.01, Figure 1). Within the AD group (n = 21), CSF SV2A was significantly correlated with synaptic density measured with [11C]UCB‐J–PET in a composite of AD‐affected regions (r = 0.65, P = 0.001, Figure 2). A regional analysis showed that CSF and PET measures of SV2A were significantly correlated broadly in the neocortex, but not in medial temporal regions such as the hippocampus, entorhinal cortex, and amygdala.ConclusionThis study supports a previous report of decreased CSF SV2A in AD. In the primary analysis, SV2A measured in CSF and SV2A measured with brain PET were strongly correlated within a group of individuals with AD, indicating that decreases in both measures may reflect synaptic loss during disease progression. Further studies will focus on longitudinal changes in CSF and PET measures of SV2A, as well as other CSF measures of synaptic and neuronal damage to investigate the neurobiology of AD.