Abstract
BackgroundWe 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.MethodsWe 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).ResultsThere 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]).ConclusionsOur 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.
Highlights
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
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]
We selected 40 patients who had received a diagnosis of probable AD dementia and matched them for age and sex with 40 patients with subjective cognitive decline (SCD), who served as control subjects, and with 40 patients with mild cognitive impairment (MCI)
Summary
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. In addition to amyloid and tau pathology, processes such as inflammation and synaptic dysfunction play an important role and may correlate more directly with cognitive decline [5,6,7]. 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. PRM is well suited for validation of explorative proteomic studies [9]
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