Synaptic biomarkers in CSF aid in diagnosis, correlate with cognition and predict progression in MCI and Alzheimer's disease

Abstract

Introduction Amyloid, Tau, and neurodegeneration biomarkers can stage Alzheimer's Disease (AD). Synaptic biomarkers may help track cognition. Methods In cognitively normal controls, Mild Cognitive Impairment (MCI) and AD, we investigated CSF biomarkers in relation to cognitive measures and as predictors of cognitive and global decline. Results There were 90 normal controls (mean age 73.0, 58% women), 57 MCI (mean age 74.3, 35% women), and 46 AD (mean age 70.7, 41% women). CSF Aβ1‐42 and Neuronal Pentraxin 2 (NPTX2) were decreased, and CSF Tau, neurogranin, and SNAP25 increased in AD versus controls. Aβ1‐42/Tau or NPTX2/Tau discriminated AD and controls best. NPTX2/Tau correlated strongly with cognition in AD and MCI and predicted a 2–3‐year decline. We replicated findings in the ADNI cohort. Discussion CSF synaptic biomarkers, particularly NPTX2, which regulates synaptic homeostasis, relate to cognition and predict progression in AD beyond Aβ1‐42 and Tau. This is relevant for prognosis and clinical trials.

Fluid Biomarkers for Synaptic Dysfunction and Loss

“…Synaptotagmin-1 ↑ = In CSF 159,161,158 Alpha-synuclein ↓ R In CSF [163][164][165][166][167][168][169][171][172][173][174][175][176][177][178]180,207,281 , in blood 189,190,278 Oligomeric = ↑ = ↑ S, P,R In CSF 169,174,197,198,207 , in blood 193,[199][200][201][202][203][204] Phosporylated = ↑ ↑ ↑ S In CSF 165,169,174,179,181,207 , in blood 185,203 Postsynaptic Neurogranin ↓ E In CSF 1,3,18,121,150,…”

“…In CSF 171,[282][283][284][285][286] , in blood 132,134,135,287,288 Heavy chain ↑ In CSF 286 Emerging Synaptophysin In CSF 44,150,235,236,242 , in blood 277…”

Single-soma transcriptomics of tangle-bearing neurons in Alzheimer’s disease reveals the signatures of tau-associated synaptic dysfunction

“…Of the 227 DE genes, 17 were dysregulated in all 5 clusters, and an additional 46 were dysregulated in 4 of the 5 clusters (MAST test; adjusted p-value < 0.05; log fold change > 0.1; detection in ≥ 20% of cells) ( Figures 6C and S7). Notably, among the commonly upregulated genes were genes encoding proteins that are biomarkers for neurodegeneration and cognitive decline in AD: NEFL, encoding neurofilament light chain; SNAP25, encoding synaptosomal-associated protein 25, a SNARE complex protein with a role in synaptic vesicle exocytosis; and SYT1, encoding synaptotagmin-1, an integral membrane protein of synaptic vesicles implicated in calcium-dependent vesicular trafficking and exocytosis (Brinkmalm et al, 2014;Davidsson et al, 1996;Galasko et al, 2019;Mattsson et al, 2017;Mattsson et al, 2019;Preische et al, 2019) (Figures 6B and S7; Table S8). Other upregulated genes related to the synaptic vesicle cycle were the synaptotagmin genes STY4 and STY11; SV2B, encoding synaptic vesicle glycoprotein 2B; and BSN, encoding the 9 presynaptic cytomatrix protein bassoon.…”

Clinical Utility of the Pathogenesis-related Proteins in Alzheimer&rsquo;s Disease

“…Before we figure out the pathway that includes pathological molecular changes and related association, we cannot make a clear definition of the timing. CSF Ng was increased in AD compared to CN or Parkinson's disease frontotemporal dementia and amyotrophic lateral sclerosis [15][16][17].…”

“…Ng/BACE1 levels were elevated in both subjective cognitive decline and mild cognitive impairment compared to healthy controls [18], and can distinguish between depression and AD among patients with similar cognitive deficits, along with the classic AD biomarkers [19]. SNAP25 increased in AD or MCI versus CN [12,15]. However Beeri [20] and Shimohama [21] indicated dementia to be associated with reductions in SNAP-25.…”