Five out of 16 plasma signaling proteins are enhanced in plasma of patients with mild cognitive impairment and Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with characteristic neuropathological changes of the brain. Great efforts have been undertaken to determine the progression of the disease and to monitor therapeutic interventions. Especially, the analysis of blood plasma had yielded incongruent results. Recently, Ray et al. (Nat. Med. 13, 2007, 1359f) identified changes of 18 signaling proteins leading to an accuracy of 90% in the diagnosis of AD. The aim of the present study was to examine 16 of these signaling proteins by quantitative Searchlight multiplex ELISA in order to determine their sensitivity and specificity in our plasma samples from AD, mild cognitive impairment (MCI), depression with and without cognitive impairment and healthy subjects. Quantitative analysis revealed an increased concentration in Biocoll isolated plasma of 5 out of these 16 proteins in MCI and AD patients compared to healthy subjects: EGF, GDNF and MIP1δ (in AD), MIP4 (in MCI) and RANTES (in MCI and AD). ROC analysis predicted a sensitivity of 65-75% and a specificity of 52-63% when comparing healthy controls versus MCI or AD. Depression without any significant cognitive deficits did not cause any significant changes. Depressed patients with significant cognitive impairment were not different from MCI patients. In conclusion, we detected a number of altered proteins that may be related to a disease specific pathophysiology. However, the overall expression pattern of plasma proteins could not be established as a biomarker to differentiate MCI from AD or from depression.

Cerebrospinal fluid and blood biomarkers in Alzheimer’s disease

“…In our study, we found reduced levels of MIP-1d in monocytes, but enhanced MIP-1d levels in plasma. These data support similar results obtained by Marksteiner et al [112] (2011) [132] .…”

“…BACE cleaves APP and releases a large N-terminal fragment (sAPPβ). The membrane-anchored frag- [73,75] Decreased [65] β-amyloid (Aβ) Decreased [45,46] No difference [79][80][81][82] No difference [47] Aβ1- 40 No difference [24] No difference [83] Increased [84] Decreased [85] Aβ1- 42 Decreased [24] Increased [83] -Aβ1-42/Aβ1-40 ratio Decreased [48] No difference [83] Decreased [78,84,86] APP ratio --Decreased [90][91][92][93] Ubiquitin Increased [24] No difference [148] BACE1 Increased [67] --Cholesterol -Decreased [94,95] Increased [96][97][98] 24S-hydroxycholesterol Increased [102] No difference [103] Decreased [104] Homocysteine -Increased [106,107,109] Epidermal growth factor -Decreased [111] Decreased [93] Increased [112] Glial cell line-derived growth factor -Decreased [111] No difference …”

“…However, results from plasma growth factor levels have been conflicting. One study reported decreased concentrations of platelet derived growth factor (PDGF), glial cell line-derived growth factor , and epidermal growth factor (EGF), while another study reported increased or unchanged plasma levels in AD patients compared to controls [111,112] . PDGF levels in platelets were similar in AD subjects and controls.…”

“…They further discriminated MCI converters from stable MCI patients or patients who converted to other dementias. Marksteiner et al [112] (2011) examined 16 of these proteins using Searchlight multiplex ELISA and found five elevated plasma proteins with a sensitivity and specificity of 65%-75% and 52%-63%. Other studies examined the same protein in plasma using alternative approaches [71] , however, replication of the results from Ray et al [111] (2007) in other cohorts was less successful.…”

Specific protein biomarker patterns for Alzheimer’s disease: improved diagnostics in progress

“…CCL, chemokine that contains a C-C motif; CXCL, chemokine that contains a C-X-C motif; G-CSF, granulocyte-colony stimulating factor; GDNF, glialderived neurotrophic factor; ICAM-1, intercellular adhesion molecule-1; IGFBP-1, insulin-like growth factor-binding protein-6; IL, interleukin; PDGF-BB, platelet-derived growth factor BB; TRAIL-R4, TNF-related apoptosis-inducing ligand receptor-4 [15]. Some of these results were verified independently, showing an increased concentration in Biocoll isolated plasma of 5 out of these proteins in MCI and AD patients compared to healthy subjects: EGF, GDNF and MIP1δ (in AD), MIP4 (in MCI), and RANTES (in MCI and AD) [16].…”