Journal Article

Synaptic proteins in CSF as potential novel biomarkers for prognosis in prodromal Alzheimer’s disease

Duits, Flora H., Zetterberg, Henrik, Blennow, Kaj, Teunissen, Charlotte E., Brinkmalm, Gunnar, Brinkmalm, Ann, Scheltens, Philip, Van der Flier, Wiesje M.

2018

Overview

Background We investigated whether a panel of 12 potential novel biomarkers consisting of proteins involved in synapse functioning and immunity would be able to distinguish patients with Alzheimer’s disease (AD) and patients with mild cognitive impairment (MCI) from control subjects. Methods We included 40 control subjects, 40 subjects with MCI, and 40 subjects with AD from the Amsterdam Dementia Cohort who were matched for age and sex (age 65 ± 5 years, 19 [48%] women). The mean follow-up of patients with MCI was 3 years. Two or three tryptic peptides per protein were analyzed in cerebrospinal fluid using parallel reaction monitoring mass spectrometry. Corresponding stable isotope-labeled peptides were added and used as reference peptides. Multilevel generalized estimating equations (GEEs) with peptides clustered per subject and per protein (as within-subject variables) were used to assess differences between diagnostic groups. To assess differential effects of individual proteins, we included the diagnosis × protein interaction in the model. Separate GEE analyses were performed to assess differences between stable patients and patients with progressive MCI (MCI-AD). Results There was a main effect for diagnosis ( p  < 0.01) and an interaction between diagnosis and protein ( p  < 0.01). Analysis stratified according to protein showed higher levels in patients with MCI for most proteins, especially in patients with MCI-AD. Chromogranin A, secretogranin II, neurexin 3, and neuropentraxin 1 showed the largest effect sizes; β values ranged from 0.53 to 0.78 for patients with MCI versus control subjects or patients with AD, and from 0.67 to 0.98 for patients with MCI-AD versus patients with stable MCI. In contrast, neurosecretory protein VGF was lower in patients with AD than in patients with MCI (ß = −0.93 [SE 0.22]) and control subjects (ß = 0.46 [SE 0.19]). Conclusions Our results suggest that several proteins involved in vesicular transport and synaptic stability are elevated in patients with MCI, especially in patients with MCI progressing to AD dementia. This may reflect early events in the AD pathophysiological cascade. These proteins may be valuable as disease stage or prognostic markers in an early symptomatic stage of the disease.

• Publisher: BioMed Central,BioMed Central Ltd,BMC
• Subject: Aged / Alzheimer Disease - cerebrospinal fluid / Alzheimer Disease - genetics / Alzheimer's disease / Amyloid beta-Peptides - cerebrospinal fluid / amyloid-beta / Apolipoproteins E - genetics / association workgroups / Biological markers / Biomarkers - cerebrospinal fluid / Biomedical and Life Sciences / Biomedicine / brain / Care and treatment / Cerebrospinal fluid / cerebrospinal-fluid biomarkers / Cognitive Dysfunction - cerebrospinal fluid / Cognitive Dysfunction - genetics / CSF biomarkers / Diagnosis / diagnostic guidelines / Female / Follow-Up Studies / Geriatric Psychiatry / Geriatrics/Gerontology / Humans / Male / Mass Spectrometry / Mental Status and Dementia Tests / Middle Aged / mild cognitive impairment / national institute / Nerve Tissue Proteins - cerebrospinal fluid / Neurology / Neurosciences / Neurovetenskaper / Parallel reaction monitoring / Peptide Fragments - cerebrospinal fluid / Phosphorylation / plasticity / Prodromal Symptoms / Prognosis / recommendations / Synapses / Synaptic proteins / tau Proteins - cerebrospinal fluid / vgf