CSF protein biomarkers predicting longitudinal reduction of CSF β-amyloid42 in cognitively healthy elders

Abstract

β-amyloid (Aβ) plaque accumulation is a hallmark of Alzheimer's disease (AD). It is believed to start many years prior to symptoms and is reflected by reduced cerebrospinal fluid (CSF) levels of the peptide Aβ1–42 (Aβ42). Here we tested the hypothesis that baseline levels of CSF proteins involved in microglia activity, synaptic function and Aβ metabolism predict the development of Aβ plaques, assessed by longitudinal CSF Aβ42 decrease in cognitively healthy people. Forty-six healthy people with three to four serial CSF samples were included (mean follow-up 3 years, range 2–4 years). There was an overall reduction in Aβ42 from a mean concentration of 211–195 pg ml−1 after 4 years. Linear mixed-effects models using longitudinal Aβ42 as the response variable, and baseline proteins as explanatory variables (n=69 proteins potentially relevant for Aβ metabolism, microglia or synaptic/neuronal function), identified 10 proteins with significant effects on longitudinal Aβ42. The most significant proteins were angiotensin-converting enzyme (ACE, P=0.009), Chromogranin A (CgA, P=0.009) and Axl receptor tyrosine kinase (AXL, P=0.009). Receiver-operating characteristic analysis identified 11 proteins with significant effects on longitudinal Aβ42 (largely overlapping with the proteins identified by linear mixed-effects models). Several proteins (including ACE, CgA and AXL) were associated with Aβ42 reduction only in subjects with normal baseline Aβ42, and not in subjects with reduced baseline Aβ42. We conclude that baseline CSF proteins related to Aβ metabolism, microglia activity or synapses predict longitudinal Aβ42 reduction in cognitively healthy elders. The finding that some proteins only predict Aβ42 reduction in subjects with normal baseline Aβ42 suggest that they predict future development of the brain Aβ pathology at the earliest stages of AD, prior to widespread development of Aβ plaques.

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

“…However, on one hand, a recent study showed that higher levels of CHGA in CSF predict future decreases in Aβ 42 in healthy elderly subjects [25]. On the other hand, a decreased level in brain tissue and CSF of patients with AD compared with control subjects has also been described [27,28,40].…”

“…The PRM panel consisted of neurosecretory protein VGF (VGF), chromogranin A (CHGA), and secretogranin 2 (SCG2), granins that are presumed to be involved in axonal or synaptic vesicle transport (the granins VGF, CHGA, and SCG2) [12]; cystatin C (CysC), a protease involved in Aβ degradation [13,14]; β 2 -microglobulin (β 2 M) and lysozyme C (LysC), proteins involved in the innate immune system [15,16]; and neurexins (NRXNs) NRXN-1, NRXN-2, and NRXN-3 as well as neuronal pentraxin 1 (NPTX1), neurofascin (NFASC), and neurocan core protein (NCANP), proteins involved in synapse formation and stabilization [17][18][19][20][21]. Several of these proteins, including VGF, CHGA, SCG2, CysC, and β 2 M, have been suggested in previous studies to be involved in AD pathology [12][13][14][22][23][24][25][26][27][28]. A pilot study that we performed after developing the PRM panel showed promising results, with lower levels for several proteins in patients with AD dementia compared with control subjects [29].…”

CSF in Alzheimer's Disease

“…Future longitudinal studies of healthy individuals will most likely help to sort out in what order these markers change in relation to plaque and tangle pathology and neurodegeneration in AD. A recent study found that several proteins in CSF, possibly associated with microglia activity, predicted longitudinal reduction of CSF Ab42 in cognitively healthy subjects, suggesting involvement of inflammatory pathways in early AD [100].…”

“…Recent data show that it is possible to identify longitudinal changes in CSF Ab42, T-tau, and P-tau in cognitively healthy controls followed with multiple lumbar punctures over several years [99][100][101], but most studies (with exceptions [99]) show that CSF AD biomarkers are essentially stable in symptomatic AD [69,102,103]. This biomarker stability (at least during short-term follow-up) may be useful in clinical trials to help identify effects of interventions, both on the intended biological target, such as altered Ab metabolism in response to an anti-Ab treatment.…”

Role of cerebrospinal fluid biomarkers to predict conversion to dementia in patients with mild cognitive impairment: a clinical cohort study

“…Several studies have shown that the relative risk of progression from MCI to AD is increased in patients with high baseline tau and p-tau, and low Aβ 1-42 with high sensitivity and specificity [7][8][9][10][11][12][13][14][15]. Following progress in research, a working group established by the National Institute of Aging in 2011 promoted a revision of the diagnostic criteria for AD and MCI, recommending the adoption of CSF biomarkers for the identification of patients with 'MCI due to AD' in research setting, i.e., patients at high risk to develop AD [16].…”