Synaptic proteins in CSF as potential novel biomarkers for prognosis in prodromal Alzheimer’s disease
Duits et al. Alzheimer's Research & Therapy
Synaptic proteins in CSF as potential novel biomarkers for prognosis in prodromal Alzheimer's disease
Flora H. Duits 0 1
Gunnar Brinkmalm 0 2 3
Charlotte E. Teunissen 1 7
Ann Brinkmalm 2 3
Philip Scheltens 1
Wiesje M. Van der Flier 1 6
Henrik Zetterberg 2 3 4 5
Kaj Blennow 2 3
0 Equal contributors
1 Alzheimer Center and Department of Neurology, Amsterdam Neuroscience, VU University Medical Center , P.O. Box 7057, 1007MB Amsterdam , The Netherlands
2 Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital , Mölndal , Sweden
3 Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at the University of Gothenburg , Mölndal , Sweden
4 UK Dementia Research Institute at UCL, University College London , London , UK
5 Department of Molecular Neuroscience, UCL Institute of Neurology , Queen Square, London , UK
6 Department of Epidemiology and Biostatistics, VU University Medical Center , Amsterdam , The Netherlands
7 Neurochemistry Laboratory and Biobank, Department of Clinical Chemistry, Amsterdam Neuroscience, VU University Medical Center , Amsterdam , The Netherlands
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.
Parallel reaction monitoring; Synaptic proteins; CSF biomarkers; Alzheimer's disease
Background
The neuropathological process of Alzheimer’s disease
(AD) is characterized by accumulation of plaques
composed of aggregated amyloid-β (Aβ) protein,
neurofibrillary tangles consisting of hyperphosphorylated tau,
and neuronal degeneration and loss [
1
]. The
cerebrospinal fluid (CSF) biomarkers of these
processes—amyloid-β 1–42 (Aβ42), total tau, and tau phosphorylated at
threonine 181 (p-tau)—show very consistent changes in
AD dementia and prodromal AD [
2
], and they have
been included as evidence for the presence of AD
pathology in research diagnostic criteria for AD [
3, 4
].
However, in addition to amyloid and tau pathology,
processes such as inflammation and synaptic
dysfunction also play an important role and may correlate
more directly with cognitive decline [
5–7
]. Hence,
biomarkers for these processes may be valuable for
disease monitoring and to predict prognosis or rate of
cognitive decline.
On the basis of in-house data derived from unbiased
CSF proteomic studies, we selected a panel of synaptic
and other proteins for analysis with parallel reaction
monitoring (PRM) MS. Explorative proteomics provides
a hypothesis-free approach for detecting a large number
of proteins and peptides in human body fluids such as
plasma and CSF [
8
]; however, the disadvantage of this
technique is the relatively poor reproducibility [
9
]. PRM
is an MS method that focuses on predefined sets of
proteins, o (...truncated)