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. 2010 Jul-Aug;16(7-8):278-86.
doi: 10.2119/molmed.2010.00015. Epub 2010 Apr 14.

Serum cholinesterase activities distinguish between stroke patients and controls and predict 12-month mortality

Einor Ben Assayag  1 , Shani Shenhar-Tsarfaty, Keren Ofek, Lilach Soreq, Irena Bova, Ludmila Shopin, Ronan M G Berg, Shlomo Berliner, Itzhak Shapira, Natan M Bornstein, Hermona Soreq
Affiliations

Serum cholinesterase activities distinguish between stroke patients and controls and predict 12-month mortality

Einor Ben Assayag et al. Mol Med. 2010 Jul-Aug.

Abstract

To date there is no diagnostic biomarker for mild stroke, although elevation of inflammatory biomarkers has been reported at early stages. Previous studies implicated acetylcholinesterase (AChE) involvement in stroke, and circulating AChE activity reflects inflammatory response, since acetylcholine suppresses inflammation. Therefore, carriers of polymorphisms that modify cholinergic activity should be particularly susceptible to inflammatory damage. Our study sought diagnostic values of AChE and Cholinergic Status (CS, the total capacity for acetylcholine hydrolysis) in suspected stroke patients. For this purpose, serum cholinesterase activities, butyrylcholinesterase-K genotype and inflammatory biomarkers were determined in 264 ischemic stroke patients and matched controls during the acute phase. AChE activities were lower (P<0.001), and butyrylcholinesterase activities were higher in patients than in controls (P=0.004). When normalized to sampling time from stroke occurrence, both cholinergic parameters were correlated with multiple inflammatory biomarkers, including fibrinogen, interleukin-6 and C-reactive protein (r=0.713, r=0.607; r=0.421, r=0.341; r=0.276, r=0.255; respectively; all P values<0.001). Furthermore, very low AChE activities predicted subsequent nonsurvival (P=0.036). Also, carriers of the unstable butyrylcholinesterase-K variant were more abundant among patients than controls, and showed reduced activity (P<0.001). Importantly, a cholinergic score combining the two cholinesterase activities discriminated between 94.3% matched pairs of patients and controls, compared with only 75% for inflammatory measures. Our findings present the power of circulation cholinesterase measurements as useful early diagnostic tools for the occurrence of stroke. Importantly, these were considerably more distinctive than the inflammatory biomarkers, albeit closely associated with them, which may open new venues for stroke diagnosis and treatment.

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Figures

Figure 1
Figure 1
AChE modulations in poststroke patients. (A) The inflammation score and (B) the cholinergic score for each of the stroke patients against that for the matched control. Reference lines represent x = Y. Pairs above the line showed positive differences between patients and controls and vice versa. Note that comparison of A to B displays superiority of the cholinergic over the inflammatory biomarkers in distinguishing stroke patients from control subjects. (C) Linear Discriminative Analysis (LDA) based on cholinergic parameters. Note clear separation of stroke patients and controls to two groups. The axes are the discriminative functions of total acetylthiocholine hydrolytic activity (F1, y axis) and AChE activity (F2, x axis). (D) Histogram of poststroke AChE reductions segregate patients (green) from controls (red) and survivors from nonsurvivors (purple). (E) Tissue sources expressing AChE include blood leukocytes. Shown are the results of microarray tests presenting the exonic expression of the AChE gene, located on the reverse genomic strand of chromosome No 7. The corresponding HG-U133_PLUS_2 probe set ID: AChE - 205377_S_AT numbers are noted from right to left and known genomic annotations (found by ensemble [http://www.ensemblestudios.com]) are marked. Bar graph: Tissues and cell types with highest expression levels of the human AChE gene. Total signal intensity of AChE mRNA exons was measured by Affymetrix exon arrays (human s_t v1) sample data sets in selected tissues (raw data downloaded from www.affymetrix.com and normalized using the Affymetrix expression console tool with PLIER algorithm). Inset: whole blood and lymph node data adopted from GeneCards’ GNF SymAtlas (Human GeneAtlas GNF1H, v1.2., Build 20080303-1059, developed by the Bioinformatics Team at GNF [http://symatlas.gnf.org] and normalized by gcRMA). Note prominent logarithmically normalized values in nucleated blood cells and that probe sets interrogating the constitutive exons 2 and 3 are labeled at considerably higher levels than other exons.
Figure 2
Figure 2
Inflammatory biomarkers correlate with serum AChE and BChE activities normalized to sampling time from stroke occurrence. Measured inflammatory biomarkers and AChE and BChE activities were divided by the time from stroke symptoms occurrence (in hours). Note that the cholinergic status (namely, total acetylthiocholine hydrolytic activity in serum) consistently showed higher correlation to each of the measured inflammatory markers.
Figure 3
Figure 3
BChE-K prevelance in stroke patients. (A) Cell and tissue sources expressing the BChE gene, located on the reverse genomic strand of chromosome 3 and corresponding HG-U133_PLUS_2 probe sets. ID: BChE – 205433_AT probe set numbers are noted from right to left and known genomic annotations (found by ensemble [http://www.ensemblestudios.com]) are marked. Bar graph and inset: Tissues and cell types with highest expression levels of the human BChE gene. Shown is total signal intensity of BChE mRNA measured by Affymetrix exon arrays (human s_t v1) sample data sets in selected tissues (raw data downloaded from www.affymetrix.com and normalized using the Affymetrix expression console tool with the PLIER algorithm). Inset: whole blood and lymph node data adapted from GeneCards’ GNF SymAtlas (Human GeneAtlas GNF1H, v1.2., Build 20080303-1059, developed by the Bioinformatics Team at GNF [http://symatlas.gnf.org] and normalized by gcRMA). Note variable intensity of labeling for different probe sets and the prominent logarithmically normalized labeling values in nucleated blood cells. The BChE gene yields only one transcript. (B) BChE gene structure, exonic composition and the 3′-terminal DNA and C-terminal amino acid sequences of BChE-U and -K. The amino acid substitution (framed) is shown above the DNA sequence. (C) Histograms of measured BChE activity in stroke patient carriers of the UU, UK and KK genotypes and matched controls. Units are nmole acetylthiocholine hydrolized/min/mL serum.
Figure 4
Figure 4
The cholinergic inflammatory mediators of stroke. Acute ischemic stroke triggers focal and systemic inflammatory responses. Vagal ACh signaling inhibits cytokine production; circulating ACh is hydrolyzed by both circulating AChE and BChE, with the latter constituting a more prominent effecter of the inflammatory consequences of stroke. Macrophages and other cytokine-producing cells express ACh receptors, which induce intracellular signals that inhibit cytokine synthesis. Afferent inflammatory signals activate an opposing cholinergic response that suppresses cytokine production and can limit inflammation.
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