Journal Mobile Options
Table of Contents
Vol. 2, No. 1, 2012
Issue release date: January–December
Open Access Gateway
Dement Geriatr Cogn Disord Extra 2012;2:353–360
(DOI:10.1159/000341780)

Serum Granulocyte Colony-Stimulating Factor and Alzheimer’s Disease

Barber R.C.a, b · Edwards M.I.e · Xiao G.f · Huebinger R.M.g · Diaz-Arrastia R.h · Wilhelmsen K.C.i · Hall J.R.a, c · O’Bryant S.E.a, d · for the Texas Alzheimer’s Research and Care Consortium
aInstitute of Aging and Alzheimer’s Disease Research and Departments of bPharmacology and Neuroscience, cPsychiatry and dInternal Medicine, University of North Texas Health Science Center, Fort Worth, Tex., eDepartment of Neurology, F. Marie Hall Institute for Rural and Community Health, Texas Tech University Health Sciences Center, Lubbock, Tex., Departments of fClinical Sciences and gSurgery, University of Texas Southwestern Medical Center, Dallas, Tex., hCenter for Neuroscience and Regenerative Medicine, Uniformed Services University of the Health Sciences, Bethesda, Md., and iDepartment of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, N.C., USA
email Corresponding Author

Abstract

Background: Granulocyte colony-stimulating factor (G-CSF) promotes the survival and function of neutrophils. G-CSF is also a neurotrophic factor, increasing neuroplasticity and suppressing apoptosis. Methods: We analyzed G-CSF levels in 197 patients with probable Alzheimer’s disease (AD) and 203 cognitively normal controls (NCs) from a longitudinal study by the Texas Alzheimer’s Research and Care Consortium (TARCC). Data were analyzed by regression with adjustment for age, education, gender and APOE4 status. Results: Serum G-CSF was significantly lower in AD patients than in NCs (β = –0.073; p = 0.008). However, among AD patients, higher serum G-CSF was significantly associated with increased disease severity, as indicated by lower Mini-Mental State Examination scores (β = –0.178; p = 0.014) and higher scores on the global Clinical Dementia Rating (CDR) scale (β = 0.170; p = 0.018) and CDR Sum of Boxes (β = 0.157; p = 0.035). Conclusions: G-CSF appears to have a complex relationship with AD pathogenesis and may reflect different pathophysiologic processes at different illness stages.


 Outline


 goto top of outline Key Words

  • Granulocyte colony-stimulating factor
  • Alzheimer’s disease
  • Inflammation
  • Serum proteins
  • Mini-Mental State Examination
  • Clinical Dementia Rating-Sum of Boxes

 goto top of outline Abstract

Background: Granulocyte colony-stimulating factor (G-CSF) promotes the survival and function of neutrophils. G-CSF is also a neurotrophic factor, increasing neuroplasticity and suppressing apoptosis. Methods: We analyzed G-CSF levels in 197 patients with probable Alzheimer’s disease (AD) and 203 cognitively normal controls (NCs) from a longitudinal study by the Texas Alzheimer’s Research and Care Consortium (TARCC). Data were analyzed by regression with adjustment for age, education, gender and APOE4 status. Results: Serum G-CSF was significantly lower in AD patients than in NCs (β = –0.073; p = 0.008). However, among AD patients, higher serum G-CSF was significantly associated with increased disease severity, as indicated by lower Mini-Mental State Examination scores (β = –0.178; p = 0.014) and higher scores on the global Clinical Dementia Rating (CDR) scale (β = 0.170; p = 0.018) and CDR Sum of Boxes (β = 0.157; p = 0.035). Conclusions: G-CSF appears to have a complex relationship with AD pathogenesis and may reflect different pathophysiologic processes at different illness stages.

Copyright © 2012 S. Karger AG, Basel


goto top of outline Introduction

Granulocyte colony-stimulating factor (G-CSF) is a hematopoietic growth factor that helps regulate the mobilization of bone marrow progenitor cells and promotes neuroprotection and neurogenesis [1,2]. G-CSF is produced by immune cells, particularly macrophages, as well as endothelial cells. Human G-CSF exists as a 174- or 180-amino-acid-long protein, with the 174-amino-acid form being more abundant and more active [3]. The G-CSF receptor is present on hematopoietic cells of the bone marrow and, when activated by G-CSF, initiates the proliferation and differentiation of progenitor cells into mature granulocytes [1]. The G-CSF receptor is also expressed by neurons in the brain and spinal cord, enabling G-CSF to act as a neurotrophic factor. In the central nervous system, G-CSF induces neurogenesis, counteracts apoptosis and increases neuroplasticity [4,5].

In rodent models of Alzheimer’s disease (AD), G-CSF treatment decreased the amyloid burden in the brain [6,7], reversed cognitive impairment [7] and reduced chronic inflammation [8]. In other studies, G-CSF administered to mice following ischemic injury has been shown to stimulate the proliferation of microglia [9].

In the present study, we sought to determine whether the serum G-CSF level significantly differs between AD and control subjects and whether serum G-CSF levels are correlated with clinical measures of disease severity.

 

goto top of outline Methods

goto top of outline Participants

Participants included 400 individuals (197 diagnosed with probable AD and 203 cognitively normal controls; NCs) enrolled in the Texas Alzheimer’s Research and Care Consortium (TARCC) longitudinal research cohort. The methodology of the TARCC project has been described in detail elsewhere. Briefly, each participant completed an annual examination consisting of a medical examination, interview, blood draw and neuropsychological testing at one of the five TARCC sites. The TARCC core neuropsychological battery consists of commonly utilized instruments in AD clinical/research settings along with measures assessing global functioning, i.e. the Mini-Mental State Examination (MMSE) [10] and the Clinical Dementia Rating (CDR) scale [11]. These data were reviewed by each site’s consensus committee, and a diagnosis was assigned according to NINCDS-ADRDA criteria [12]. NCs were judged to be within normal limits on neuropsychological testing by consensus review. Participants with AD were largely in the mild-to-moderate range. The TARCC project has Institutional Review Board approval at all member institutions, and all participants and/or caregivers signed written informed consent documents.

goto top of outline Assays

Non-fasting samples were collected in serum-separating tubes during clinical evaluations, allowed to clot at room temperature for 1 h, centrifuged, aliquoted and stored at –80°C in polypropylene vials. Frozen samples were sent to Rules Based Medicine (www.rulesbasedmedicine.com, Austin, Tex., USA), where they were thawed for assay without additional freeze-thaw cycles. Rules Based Medicine conducted a multiplex immunoassay via their human Multi-Analyte Profiling (human MAP) technology. Multiple proteins, including G-CSF, were quantified through multiplex fluorescent immunoassay utilizing colored microspheres with protein-specific antibodies. For G-CSF, the least detectable dose was 5 pg/ml, inter-run coefficient of variation was <10%, dynamic range was 1–5,000 pg/ml, overall spiked standard recovery for serum was 70% and cross-reactivity with other human MAP analytes was <1%. Assays conducted by this company utilizing this platform, including TARCC data, have been published elsewhere [13,14].

goto top of outline Analyses

Statistical analyses were conducted using SPSS version 19.0 (IBM). Unadjusted analyses were conducted by either t test for continuous or Mann-Whitney U test for categorical variables. Serum G-CSF levels were compared across diagnostic categories (AD vs. NC), and associations between G-CSF levels and disease severity (MMSE and CDR scores) were assessed by multivariate regression. All regression models included age, sex, years of education, race and APOE4 carrier status as covariates. Statistical significance was declared for p values <0.05. In follow-up analyses, the sample was stratified on APOE4 carrier status (–/– vs. –/+ and +/+), and the analyses described above were repeated.

 

goto top of outline Results

Demographic characteristics of the study population are shown in table 1. Relative to controls, AD patients did not significantly differ with respect to sex, race or Hispanic ethnicity; however, they were significantly older (median age, 79 vs. 70 years; p < 0.001), less educated (median years of education, 14 vs. 16; p < 0.001) and more likely to carry one or more copies of the APOE ε4 allele (APOE4 carriers, 13.7 vs. 2.5%; p < 0.001).

TAB01
Table 1. Demographic information of the 400 participants in the TARCC longitudinal research cohort

Median serum G-CSF levels were significantly lower in AD cases compared to controls (8.1 vs. 9.9 pg/ml, respectively; table 1). G-CSF remained significantly associated with diagnostic category (β = –0.073; p = 0.008) following adjustment for age, sex, education and APOE status (table 2). To test for residual confounding by the APOE4 allele, an analysis was run after stratification of the sample on APOE4 status. Serum G-CSF was not significantly associated with disease status in either the APOE4-positive or APOE4-negative group. However, the p values were marginal (0.053 and 0.077 in APOE4-negative and APOE4-positive individuals, respectively), and the trends were consistent with those observed in the unstratified sample (data not presented).

TAB02
Table 2. Odds ratio for disease status following adjustment for multiple factors as determined by multivariate logistic regression

Among AD participants only (n = 197), higher serum G-CSF levels were negatively associated with lower (worse) scores on the MMSE (β = –0.178; p = 0.014; table 3) and positively associated with higher (worse) scores on the CDR Global (β = 0.170; p = 0.018; table 4) and CDR Sum of Boxes (β = 0.153; p = 0.035; table 5).

TAB03
Table 3. Multivariate logistic regression for MMSE scores of participants in the TARCC longitudinal cohort with a diagnosis of probable AD

TAB04
Table 4. Multivariate logistic regression for global CDR scores of participants in the TARCC longitudinal cohort with a diagnosis of probable AD

TAB05
Table 5. Multivariate logistic regression for CDR-Sum of Boxes scores of participants in the TARCC longitudinal cohort with a diagnosis of probable AD

In post-hoc analyses, serum G-CSF levels were tested for association with individual neuropsychiatric test score by multivariate logistic regression. Serum G-CSF concentration was significantly associated with only digit span among AD participants and delayed logical memory among controls (table 6). In an attempt to resolve the impact of a number of key processes that have been shown to be important to AD pathology, we performed a set of stratified analyses. First, we selected proteins that were representative of inflammation (C-reactive protein; CRP), coagulation (thrombopoietin; THP) and neurotrophic factors (brain derived neurotrophic factor; BDNF). Next, we stratified the participants based upon tertiles for each of these proteins. Finally, we evaluated the association between G-CSF and diagnostic status (AD vs. NC) for participants within each group. Serum G-CSF levels were significantly associated with diagnostic status for participants in the mid-tertile for THP and BDNF. In contrast, G-CSF was associated with diagnostic status only for participants in the high-tertile for CRP (table 7).

TAB06
Table 6. Multivariate logistic regression for association between serum G-CSF levels and neuropsychological test scores, following adjustment for age, gender, years of education and APOE4 status

TAB07
Table 7. Results for G-CSF from multivariate logistic regression analysis of G-CSF and MMSE scores among AD patients following stratification into tertiles on brain-derived neurotrophic factor (BDNF), C-reactive protein (CRP) and thrombopoietin

 

goto top of outline Discussion

In addition to hematopoietic functions, G-CSF has a number of neuroprotective effects. With respect to AD, G-CSF increases the number of microglia, decreases β-amyloid deposition and reverses cognitive impairment in a mouse model [15,16]. In the present work, we sought to determine whether serum levels of G-CSF are associated with a diagnosis of AD or with disease severity among individuals with a diagnosis of probable AD.

In our primarily Caucasian cohort of individuals with a diagnosis of probable AD and NCs from Texas, we observed significantly lower serum levels of G-CSF protein among AD cases than controls. This observation is in agreement with others [17]. In follow-up analyses in the same cohort, we observed a significant positive association between serum G-CSF and disease severity, as measured by MMSE and CDR scores.

In agreement with the present study, Laske et al. [17] reported lower plasma G-CSF levels in early AD subjects relative to controls. Furthermore, these authors observed that, among AD patients, plasma G-CSF showed a significant inverse correlation with amyloid-β (Aβ1–42) levels in cerebrospinal fluid. Our results in a larger cohort confirm part of this prior work as we observed a significantly lower level of serum G-CSF among AD patients, compared to NCs. However, in contrast to Laske et al. [17], we found that increased serum G-CSF was significantly associated with greater disease severity. This difference between the present findings and those of Laske et al. [17] may be due to statistical power and sample size issues. While the previously published study analyzed samples from a total of 100 subjects (50 AD cases, 50 NCs), our results were based on 400 participants. Agreement in the direction of the association between G-CSF levels and increased disease severity among AD participants increases confidence in the results of the present study.

Other researchers, including ourselves, have observed an impact of APOE4 status on associations between various biomarkers and disease status [18]. However, in this instance, carriage of the APOE4 allele did not seem to influence the results. Although stratification of the sample negatively affected the tests by reducing the sample size and hence statistical power, all trends were in the same direction in both stratified and unstratified analyses.

 

goto top of outline Conclusions

In light of the neurotrophic and neuroprotective role of G-CSF, our results are consistent with the hypothesis that reduced G-CSF abundance contributes to AD pathology. Taken together, these observations raise the possibility that G-CSF is dysregulated early in the disease process and that the elevation in G-CSF observed in more advanced disease may represent a compensatory response. Future work by TARCC scientists will investigate this possibility through the analysis of longitudinal samples collected from the same participants over several years. These findings have implications for the design of clinical trials of G-CSF for the prevention or treatment of AD.

 

goto top of outline Acknowledgements

This study was made possible by the Texas Alzheimer’s Research and Care Consortium (TARCC) funded by the state of Texas through the Texas Council on Alzheimer’s Disease and Related Disorders. Investigators at the University of Texas Southwestern Medical Center at Dallas also acknowledge support from the UTSW Alzheimer’s Disease Center (NIH, NIA grant P30AG12300).

 

goto top of outline Disclosure Statement

The authors have no actual or potential conflict of interest.


 goto top of outline Footnotes

Footnote 1
Investigators from the Texas Alzheimer’s Research and Care Consortium: Baylor College of Medicine: Rachelle Doody, MD, PhD, Susan Rountree, MD, Valory Pavlik, PhD, Wen Chan, PhD, Paul Massman, PhD, Eveleen Darby, Tracy Evans, RN, and Aisha Khaleeq; Texas Tech University Health Science Center: Benjamin Williams, MD, Gregory Schrimsher, PhD, Andrew Dentino, MD, and Ronnie Orozco; University of North Texas Health Science Center: Thomas Fairchild, PhD, Janice Knebl, DO, Douglas Mains, and Lisa Alvarez; University of Texas Southwestern Medical Center: Perrie Adams, PhD, Roger Rosenberg, MD, Myron Weiner, MD, Mary Quiceno, MD, Joan Reisch, PhD, Doris Svetlik, Amy Werry, and Janet Smith; University of Texas Health Science Center – San Antonio: Donald Royall, MD, Raymond Palmer, PhD, and Marsha Polk.


 goto top of outline References
  1. Thomas J, Liu F, Link DC: Mechanisms of mobilization of hematopoietic progenitors with granulocyte colony-stimulating factor. Curr Opin Hematol 2002;9:183–189.

    External Resources

  2. Schneider A, Kuhn HG, Schäbitz WR: A role for G-CSF (granulocyte-colony stimulating factor) in the central nervous system. Cell Cycle 2005;4:1753–1757.
  3. Asano S: Human granulocyte colony-stimulating factor: its basic aspects and clinical applications. Am J Pediatr Hematol Oncol 1991;13:400–413.
  4. Schneider A, Krüger C, Steigleder T, et al: The hematopoietic factor G-CSF is a neuronal ligand that counteracts programmed cell death and drives neurogenesis. J Clin Invest 2005;115:2083–2098.
  5. Pitzer C, Krüger C, Plaas C, et al: Granulocyte-colony stimulating factor improves outcome in a mouse model of amyotrophic lateral sclerosis. Brain 2008;131:3335–3347.

    External Resources

  6. Li B, Gonzalez-Toledo ME, Piao CS, et al: Stem cell factor and granulocyte-colony stimulating factor reduce beta-amyloid deposits in the brains of APP/PS1 transgenic mice. Alzheimers Res Ther 2011;3:8.

    External Resources

  7. Sanchez-Ramos J, Song S, Sava V, et al: Granulocyte colony stimulating factor decreases brain amyloid burden and reverses cognitive impairment in Alzheimer’s mice. Neuroscience 2009;163:55–72.
  8. Jiang H, Liu CX, Feng JB, et al: Granulocyte colony-stimulating factor attenuates chronic neuroinflammation in the brain of amyloid precursor protein transgenic mice: an Alzheimer’s disease mouse model. J Int Med Res 2010;38:1305–1312.
  9. Bartolini A, Vigliani MC, Magrassi L, et al: G-CSF administration to adult mice stimulates the proliferation of microglia but does not modify the outcome of ischemic injury. Neurobiol Dis 2011;41:640–649.
  10. Folstein MF, Folstein SE, McHugh PR: ‘Mini-mental state’. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189–198.
  11. Morris JC: The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology 1993;43:2412–2414.
  12. McKhann G, Drachman D, Folstein M, et al: Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984;34:939–944.
  13. Simón-Sánchez J, Singleton A: Genome-wide association studies in neurological disorders. Lancet Neurol 2008;7:1067–1072.
  14. O’Bryant SE, Xiao G, Barber R, et al: A serum protein-based algorithm for the detection of Alzheimer disease. Arch Neurol 2010;67:1077–1081.

    External Resources

  15. Kannengiesser K, Maaser C, Kucharzik T: Molecular pathogenesis of inflammatory bowel disease: relevance for novel therapies. Per Med 2008;5:609–626.

    External Resources

  16. Borel C, Antonarakis SE: Functional genetic variation of human miRNAs and phenotypic consequences. Mamm Genome 2008;19:503–509.
  17. Laske C, Stellos K, Stransky E, et al: Decreased plasma levels of granulocyte-colony stimulating factor (G-CSF) in patients with early Alzheimer’s disease. J Alzheimers Dis 2009;17:115–123.
  18. Leoni V: The effect of apolipoprotein E (ApoE) genotype on biomarkers of amyloidogenesis, tau pathology and neurodegeneration in Alzheimer’s disease. Clin Chem Lab Med 2011;49:375–383.

 goto top of outline Author Contacts

Robert C. Barber, PhD
Institute for Aging and Alzheimer’s Disease Research
University of North Texas Health Science Center
Fort Worth, TX 76107 (USA)
Tel. +1 817 735 2506, E-Mail robert.barber@unthsc.edu


 goto top of outline Article Information

Published online: August 29, 2012
Number of Print Pages : 8
Number of Figures : 0, Number of Tables : 7, Number of References : 18


 goto top of outline Publication Details

Dementia and Geriatric Cognitive Disorders Extra

Vol. 2, No. 1, Year 2012 (Cover Date: January-August)

Journal Editor: Chan-Palay V. (Boston, Mass.)
ISSN: 1664-5464 (Print), eISSN: 1664-5464 (Online)

For additional information: http://www.karger.com/DEE


Open Access License / Drug Dosage / Disclaimer

Open Access License: This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license), applicable to the online version of the article only. Distribution permitted for non-commercial purposes only.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Background: Granulocyte colony-stimulating factor (G-CSF) promotes the survival and function of neutrophils. G-CSF is also a neurotrophic factor, increasing neuroplasticity and suppressing apoptosis. Methods: We analyzed G-CSF levels in 197 patients with probable Alzheimer’s disease (AD) and 203 cognitively normal controls (NCs) from a longitudinal study by the Texas Alzheimer’s Research and Care Consortium (TARCC). Data were analyzed by regression with adjustment for age, education, gender and APOE4 status. Results: Serum G-CSF was significantly lower in AD patients than in NCs (β = –0.073; p = 0.008). However, among AD patients, higher serum G-CSF was significantly associated with increased disease severity, as indicated by lower Mini-Mental State Examination scores (β = –0.178; p = 0.014) and higher scores on the global Clinical Dementia Rating (CDR) scale (β = 0.170; p = 0.018) and CDR Sum of Boxes (β = 0.157; p = 0.035). Conclusions: G-CSF appears to have a complex relationship with AD pathogenesis and may reflect different pathophysiologic processes at different illness stages.



 goto top of outline Author Contacts

Robert C. Barber, PhD
Institute for Aging and Alzheimer’s Disease Research
University of North Texas Health Science Center
Fort Worth, TX 76107 (USA)
Tel. +1 817 735 2506, E-Mail robert.barber@unthsc.edu


 goto top of outline Article Information

Published online: August 29, 2012
Number of Print Pages : 8
Number of Figures : 0, Number of Tables : 7, Number of References : 18


 goto top of outline Publication Details

Dementia and Geriatric Cognitive Disorders Extra

Vol. 2, No. 1, Year 2012 (Cover Date: January-August)

Journal Editor: Chan-Palay V. (Boston, Mass.)
ISSN: 1664-5464 (Print), eISSN: 1664-5464 (Online)

For additional information: http://www.karger.com/DEE


Open Access License / Drug Dosage

Open Access License: This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license), applicable to the online version of the article only. Distribution permitted for non-commercial purposes only.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Thomas J, Liu F, Link DC: Mechanisms of mobilization of hematopoietic progenitors with granulocyte colony-stimulating factor. Curr Opin Hematol 2002;9:183–189.

    External Resources

  2. Schneider A, Kuhn HG, Schäbitz WR: A role for G-CSF (granulocyte-colony stimulating factor) in the central nervous system. Cell Cycle 2005;4:1753–1757.
  3. Asano S: Human granulocyte colony-stimulating factor: its basic aspects and clinical applications. Am J Pediatr Hematol Oncol 1991;13:400–413.
  4. Schneider A, Krüger C, Steigleder T, et al: The hematopoietic factor G-CSF is a neuronal ligand that counteracts programmed cell death and drives neurogenesis. J Clin Invest 2005;115:2083–2098.
  5. Pitzer C, Krüger C, Plaas C, et al: Granulocyte-colony stimulating factor improves outcome in a mouse model of amyotrophic lateral sclerosis. Brain 2008;131:3335–3347.

    External Resources

  6. Li B, Gonzalez-Toledo ME, Piao CS, et al: Stem cell factor and granulocyte-colony stimulating factor reduce beta-amyloid deposits in the brains of APP/PS1 transgenic mice. Alzheimers Res Ther 2011;3:8.

    External Resources

  7. Sanchez-Ramos J, Song S, Sava V, et al: Granulocyte colony stimulating factor decreases brain amyloid burden and reverses cognitive impairment in Alzheimer’s mice. Neuroscience 2009;163:55–72.
  8. Jiang H, Liu CX, Feng JB, et al: Granulocyte colony-stimulating factor attenuates chronic neuroinflammation in the brain of amyloid precursor protein transgenic mice: an Alzheimer’s disease mouse model. J Int Med Res 2010;38:1305–1312.
  9. Bartolini A, Vigliani MC, Magrassi L, et al: G-CSF administration to adult mice stimulates the proliferation of microglia but does not modify the outcome of ischemic injury. Neurobiol Dis 2011;41:640–649.
  10. Folstein MF, Folstein SE, McHugh PR: ‘Mini-mental state’. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189–198.
  11. Morris JC: The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology 1993;43:2412–2414.
  12. McKhann G, Drachman D, Folstein M, et al: Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984;34:939–944.
  13. Simón-Sánchez J, Singleton A: Genome-wide association studies in neurological disorders. Lancet Neurol 2008;7:1067–1072.
  14. O’Bryant SE, Xiao G, Barber R, et al: A serum protein-based algorithm for the detection of Alzheimer disease. Arch Neurol 2010;67:1077–1081.

    External Resources

  15. Kannengiesser K, Maaser C, Kucharzik T: Molecular pathogenesis of inflammatory bowel disease: relevance for novel therapies. Per Med 2008;5:609–626.

    External Resources

  16. Borel C, Antonarakis SE: Functional genetic variation of human miRNAs and phenotypic consequences. Mamm Genome 2008;19:503–509.
  17. Laske C, Stellos K, Stransky E, et al: Decreased plasma levels of granulocyte-colony stimulating factor (G-CSF) in patients with early Alzheimer’s disease. J Alzheimers Dis 2009;17:115–123.
  18. Leoni V: The effect of apolipoprotein E (ApoE) genotype on biomarkers of amyloidogenesis, tau pathology and neurodegeneration in Alzheimer’s disease. Clin Chem Lab Med 2011;49:375–383.