Journals of Gerontology Series A: Biological Sciences and Medical Sciences Large Type Edition
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Blain, H.
Right arrow Articles by Jeandel, C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Blain, H.
Right arrow Articles by Jeandel, C.
The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 57:M241-M245 (2002)
© 2002 The Gerontological Society of America

Arterial Wall Production of Cytokines in Giant Cell Arteritis

Results of a Pilot Study Using Human Temporal Artery Cultures

Hubert Blaina, Idritia Abdelmouttalebb, Joël Belmind, Arielle Blaina, Jacques Floquetc, Jean-Louis Guéantb and Claude Jeandela

a Department of Internal Medicine and Geriatrics, University Hospital, Montpellier, France
b Laboratory of Biology in Nutrition, Nancy-Brabois University Hospital, Vandoeuvre-lès-Nancy, France
c Department of Histology, Nancy-Brabois University Hospital, Vandoeuvre-lès-Nancy, France
d Department of Internal Medicine and Geriatrics, René Muret-Bigottini Hospital, Sevran, France

Claude Jeandel, Service de Médecine Interne-Gériatrie, Centre de Prévention et de Traitement des Maladies du Vieillissement, 39 Avenue Charles Flahault, 34295 Montpellier Cedex 5, France E-mail: c-jeandel{at}chu-montpellier.fr.


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
Background. Giant cell arteritis (GCA) is a subacute periarteritis predominantly affecting segments of the external carotids of elderly patients. Vasculitic lesions in GCA samples might be characterized by in situ production of cytokines mRNA, indicative of macrophage and T-cell activation. However, whether the cytokine production of vessels with arteritis differs from that of vessels exposed to inflammatory conditions that originate peripheral to the vessel remains unknown.

Methods. We investigated cytokine and soluble receptor cytokine production in blood samples and cultures of human temporal arteries from 22 consecutive patients (mean age 77 ± 6 years) further investigated for possible diagnosis of GCA: 7 patients had GCA and 15 had neither GCA nor vasculitis but had other inflammatory, infectious, or malignant diseases (controls). The production of cytokines and soluble cytokine receptors in the supernatants of cultures of 3-mm segments of temporal artery specimens, before and after lipopolysaccharide (LPS) stimulation (10 ng/ml and 10 µg/ml) and in serum, was quantified using sandwich enzyme-linked immunosorbent assay (ELISA).

Results. Cytokine production by temporal arteries increased significantly and in a dose-dependent manner (p < .01) after LPS stimulation in all patients studied, suggesting that the system is methodologically functional. Despite a large interindividual variation, we found similar differences in cytokine production before and after stimulation by 10 ng/ml and 10 µg/ml LPS between both groups: temporal arteries of GCA patients produced more interleukin (IL)-1ß (p < .05) and IFN{gamma} (nonsignificant) and less tumor necrosis factor (TNF){alpha} (p < .05) and IL-6 (nonsignificant) than temporal arteries of controls. The levels of TNF{alpha} (p < .05) and IL-6 soluble receptor (p < .05) were significantly lower in GCA patients as compared with controls in blood samples, whereas levels of cytokines in temporal artery and in blood samples were not significantly correlated at the individual level in both groups.

Conclusions. The present pilot study, which requires further confirmation on a larger number of well-defined patients with GCA, suggests that a specific arterial cytokine production profile might exist in GCA (high IL-1ß ± IFN{gamma} and low TNF{alpha}), addresses the question of the mechanisms by which IL-1ß and TNF{alpha} might be differentially regulated at the level of the arterial cell wall, and supports the view that cultures of the temporal artery might be an interesting tool for evaluating the role of cytokines in GCA pathogenesis.

CYTOKINES are a family of polypeptides involved in a complex intercellular signaling network. Most cytokines are activated in a cascade manner and play a major role in inflammatory processes. Cytokines are the main stimulators of acute-phase protein production, fever, and anorexia associated with inflammation. Moreover, they participate in the cooperation between immune cells and regulate the immune response.

Giant cell arteritis (GCA) is a subacute perivasculitis that predominantly affects medium- and large-size arteries of elderly patients. In this disease, arterial biopsies reveal inflammatory infiltration by T lymphocytes, multinucleated giant cells (arising from the fusion of monocytes), and macrophages that express the class II major histocompatibility complex antigen HLA-DR, interleukin (IL)-2 receptors, and adhesin molecules (1)(2)(3)(4)(5)(6). Cytokines have been hypothesized to be of crucial significance in the pathogenesis of GCA because vasculitic lesions in GCA samples might be characterized by in situ production of IL-1ß, IL-6, and transforming growth factor mRNA, indicative of macrophage activation, and by interferon-{gamma} (IFN{gamma}) and IL-2 mRNA, indicative of selective T- or NK-cells activation (7). Furthermore, among the proinflammatory cytokines, high serum IL-6, predominantly secreted by peripheral blood monocytes (8), has been reported in GCA before treatment (9)(10)(11) and has been recently considered to be more sensitive than erythrocyte sedimentation rate (ESR) for indicating disease activity in untreated and treated GCA patients (12).

Although immune cells are the main source and target of cytokines, other cell types, especially endothelial cells, are responsive to and release cytokines and are known to be involved in different inflammatory processes, including infectious or malignant diseases. These inflammatory conditions may activate the endothelial cells and so alter their cytokine production (13)(14)(15).

To address the question whether the cytokine production of vessels with arteritis differs from that of vessels exposed to inflammatory conditions that originate peripheral to the vessel, we set up a culture system of human temporal arteries adapted from a rat aorta culture model (16) and compared the levels of cytokines and soluble cytokine receptors produced at baseline and after stimulation with lipopolysaccharide (LPS) in the supernatants of temporal artery cultures from a group of GCA patients and from patients with other systemic inflammatory diseases. In each group of patients, we compared the baseline level of cytokines and soluble cytokine receptors in both temporal artery cultures and in blood samples.


   Methods
Top
 Abstract
 Methods
Results
 Discussion
 References
 
Patients
Twenty-two consecutive patients hospitalized in several departments of internal medicine and geriatrics underwent temporal artery biopsy prescribed by their physician to establish a possible diagnosis of GCA. Seven patients had GCA on the basis of typical clinical and histological signs of the disease (GCA patients). The remaining 15 had neither histological signs of GCA nor vasculitis, nor symptoms requiring steroid treatment after a 1-year follow-up, but had other systemic inflammatory diseases, especially infectious or malignant diseases (control patients).

Protocol
Blood and temporal artery samples were obtained from all subjects. Temporal artery biopsies were performed by the main investigator of the study as soon as the diagnosis of GCA was suspected. Steroid treatment was initiated immediately after the biopsy if necessary.

Plasma fibrinogen level was determined by a clotting assay according to the Clauss method. C-reactive protein (CRP) and orosomucoid were measured by immunonephelemetry. ESR was measured by the Westergren method. Aliquots of plasma were frozen and stored at –70°C for cytokine determination.

A temporal artery biopsy was performed in all patients according to a standardized procedure under sterile conditions. After local analgesia, temporal skin was incised, and about 2 cm of a branch of temporal artery was excised. A 1-cm segment of the temporal artery was taken for routine histological study. The remaining part (1 cm) was cut into three segments, each 3 mm in length, fresh-weighed, and rinsed in Dulbecco's modified Eagles medium (DMEM) to remove traces of blood. Each segment was placed into a well (>10 mg tissue per well) containing 500 µl DMEM with 1% fetal calf serum, 100 U/ml penicillin, and 100 µg/ml streptomycin. LPS from Escherichia coli (Sigma) was added to well 2 (10 ng/ml) (LPS1) and to well 3 (10 µg/ml) (LPS2) for each patient. Vessels were kept at 37°C in an incubator under 5% CO2 for 20 hours. Aliquot samples of 240 µl supernatant specimens from each well were immediately frozen at –80°C. Production of cytokine and soluble cytokine receptors was expressed by mg of arterial tissue.

The levels of tumor necrosis factor alpha (TNF{alpha}), IL-1ß, IL-6, IL-2, soluble receptors of IL-6 (RIL-6) and IL-2 (RIL-2), and IFN{gamma} were determined in plasma and in the supernatant of temporal artery cultures using a sandwich ELISA according to the manufacturer (Immunotech International). The sensitivity and specificity of bioassays were >97%, and the coefficient of variation was <6%. Detection thresholds were 5 pg/ml for IL-2, IL-6, IFN{gamma}, and IL-1ß; 5 pg/ml for plasma TNF{alpha}; 10 pg/ml for cultured temporal artery supernatant TNF{alpha}; 5 pM for RIL-2; 10 ng/ml for plasma; and 3 ng/ml for artery supernatant RIL-6.

Statistical Data Analysis
Data are expressed as mean ± SEM unless otherwise specified. The nonparametric Mann-Whitney test was used to compare the quantitative data of GCA and control patients as is usually done in cases of small-population and non-Gaussian distribution analyses.

Cytokine concentrations in supernatants were compared by analysis of covariance (ANCOVA) to study the effects of the group (GCA or controls) and LPS stimulation [LPS0 (no LPS), LPS1 (10 ng/ml), and LPS2 (10 µg/ml)]. Log-transformed variables were used to assume normal distribution for cytokine concentration. Percent increases in cytokine level by LPS at both concentrations (stimulated-baseline/baseline) were also compared in both groups.

The relationship between cytokine production in blood samples and in cultured temporal arteries at baseline condition and between the log of these values was studied in GCA and control patients by ANOVA with p < .05 considered as significant.


   Results
Top
 Abstract
 Methods
 Results
Discussion
 References
 
No significant difference was observed between both groups in terms of age. Patients with GCA were significantly more likely to be men than were controls (p < .001). Patients with GCA exhibited fever in four cases (57%), headache in three cases (43%), weight loss in two cases (28%), and jaw claudication, visual symptoms, scalp tenderness, or systemic arteritis in one case (14%). Control patients exhibited fever in 10 cases (66%), headache in five cases (33%), polyarthritis in one case (6%), and/or weight loss in two cases (12%), related to an infectious disease in eight cases (viral encephalitis in one case, severe influenza in one case, endocarditis in two cases, pulmonary tuberculosis in one case, atypical pneumonia in two cases, hip prosthesis infection in one case) (53%), cancer in four cases (meningioma in one case, lung carcinoma in two cases, hepatocarcinoma in one case) (26%), rheumatoid arthritis in one case, drug-induced hepatitis in one case, and thyroiditis in one case (6%). No significant difference was observed between the values of routine inflammatory parameters obtained in GCA and control patients (Table 1 ).


View this table:
[in this window]
[in a new window]
  		Table 1. Main Characteristics of Patients With Giant Cell Arteritis (GCA) and Controls (Mean ± SD)

 
Mean weight of the 3-mm segments did not differ significantly between GCA patients (4.22 ± 3.73 mg) and controls (3.52 ± 2.95 mg).

Table 2 shows the comparative cytokine profiles in temporal artery supernatants of GCA and control patients and the effect of LPS stimulation on in situ cytokine production. The LPS effect was dose-dependent in each case. Percent increase of TNF{alpha} after LPS stimulation was not significantly different in GCA patients and controls (58.3 ± 25.6% vs 37.8 ± 13.6% respectively, for LPS 10 ng/ml; 433.3 ± 212.1% vs 390.2 ± 187.7% respectively, for LPS 10 µg/ml). Percent increase of IL-1ß levels after 10 ng/ml LPS stimulation was not significantly different in GCA patients and controls (21.2 ± 10.6% vs 29.8 ± 13.5%) and was higher in controls than in GCA patients after 10 µg/ml LPS stimulation (207.8 ± 92.6% vs 31.9 ± 17.9%, respectively) (p < .001). GCA patients had higher levels of IL-1ß (p < .05) and IFN{gamma} (nonsignificant) and lower levels of TNF{alpha} (p < .05) and IL-6 (nonsignificant), at baseline and after LPS stimulation. IL-2, RIL-2, and RIL-6 were undetectable.


View this table:
[in this window]
[in a new window]
  		Table 2. Cytokine Production in Artery Culture Supernatants From Patients With Giant Cell Arteritis (GCA) and Controls Before and After Lipopolysaccharide (LPS) Stimulation (Arterial Production is Expressed by mg Arterial Tissue)

 
Mean values of blood cytokine concentrations obtained in both groups of patients are shown in Table 3 . As compared with controls, GCA patients had lower plasma TNF{alpha} (p < .05) and RIL-6 (p < .05) values and a nonsignificant trend to increased values of IL-2, RIL-2, and IFN{gamma} and decreased values of IL-6. IL-1ß was undetectable in all plasmas.


View this table:
[in this window]
[in a new window]
  		Table 3. Cytokine Concentration in Patients With Giant Cell Arteritis (GCA) and Controls in the Blood Samples

 
Levels of IL-6, TNF{alpha}, and IFN{gamma} in blood and in the arterial segment supernatants were not significantly correlated at baseline in paired samples. Cytokine levels in blood and at baseline or stimulated supernatants did not correlate with ESR, CRP, log ESR, and log CRP (data not shown).


   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
The organoid culture system is an interesting model with great potential for many experimental studies on vessels because it preserves in vivo cell-to-cell and cell-to-matrix interactions and it allows the study of living cells under basal condition and after activation. In mice, cultures of arteries have been particularly used to examine the effects of hypertension on arterial wall (17) and mechanisms involved in arterial remodeling and vasoactivity (18). In a previous study, we demonstrated that cultures of rat aorta were relevant models to examine the effects of aging on artery cytokine production (16). In the present study, we adapted this cultured system to human temporal arteries and showed differences in cytokine production by arterial wall between GCA and controls with other inflammatory diseases, suggesting that this model might be a useful tool for evaluating the role of cytokines in GCA pathogenesis.

We found that levels of cytokines in arterial segment supernatants increased significantly and in a dose-dependent manner after LPS stimulation in all patients studied. Although LPS doses used were high and the amount of cytokines after such a powerful stimulation is probably unrelated to GCA pathogenesis, these data strongly suggest that the system is methodologically functional. Thus, differences of cytokine levels in arterial segment supernatants between GCA and control patients were found to be quite similar before and after stimulation by 10 ng/ml and 10 µg/ml LPS, suggesting that 3 mm is a sufficient length of artery tissue to obtain cultured segments with a comparable degree and extent of inflammation. This point is of crucial importance because of the discontinuous nature of vessel wall inflammation in GCA. We also observed significant differences between cytokine levels in blood samples and in arterial segment supernatants in paired samples, suggesting that cytokines measured in the supernatant of temporal artery cultures were produced by arterial wall cells and not by blood cells.

However, we found a large interindividual variation in cytokine levels in arterial segment supernatants from both GCA and control patients, who had, however, quite similar levels of C-reactive protein, orosomucoid, and fibrin. Besides the intrinsic variability of the method, dispersion of data might be due to the heterogeneous clinical characteristics of the controls, which included patients with infection, cancer, and immune disorders, and of the GCA patients because a possible correlation between the clinical presentation of GCA and cytokine mRNA expression in affected temporal arteries has been reported (19). The variability of results, which supports the concept that several forms of GCA might exist (19)(20)(21)(22), also suggests that, with this human temporal artery culture model as well as for other ex vivo models (16), data from an appropriate number of GCA and control patients are necessary to make meaningful comparisons of cytokine levels in arterial segment supernatants. One other explanation of the heterogeneous results in controls is that some patients may have been misclassified, because a single contiguous, 1-cm, unilateral sampling of artery is not sufficient to rule out categorically temporal arteritis. However, the 1-year follow-up renders it probable that the proportion of controls misclassified is small.

Even though the number of GCA patients and inflammatory controls was too small to permit drawing conclusions, we found that both baseline and activated cytokine level in the arterial segment supernatants from GCA patients showed similar differences as compared with controls, exhibiting a significantly higher IL-1ß and lower TNF{alpha} level and a trend to higher IFN{gamma} and lower IL-6 production. This finding, which must be analyzed according to the limitations discussed above, supports the hypothesis that a specific cytokine activation profile might occur in the arterial wall in GCA patients, involving predominantly IL-1ß and IFN{gamma} (7). The high interindividual variation in the arterial segment supernatants of IL-1ß and IFN{gamma} in GCA patients, perhaps explained by different inflammatory pathways leading to different clinical phenotypes (7)(22) and structural changes in arterial wall in GCA patients (23), suggests the interest of further investigating the correlation between arterial wall cytokine production with the clinical and histological presentation of GCA patients.

Like previous studies in normal human and animal arterial explants, we observed a basal level of IFN{gamma}, IL-1ß, IL-6, and TNF{alpha} in the supernatants from noninflamed temporal arteries of several control patients (8)(13)(24)(25). Because the increase in arterial wall production of cytokines has been shown with aging (13) and atherosclerosis (24)(25)(26), studies should be performed with GCA patients and controls pair-matched for age and vascular risk factors to provide meaningful comparisons of cytokine levels in the arterial segment supernatants.

The present results obtained with a human temporal artery culture model strongly suggest that GCA might be characterized by a specific temporal artery cytokine secretion profile (high IL-1ß and/or IFN{gamma}, low TNF{alpha}). Although these data require further confirmation on a larger number of well-defined GCA patients, they address the question of the mechanisms by which two macrophage-derived cytokines (IL-1ß and TNF{alpha}) might be differentially regulated at the level of arterial cell wall and support the view that the study of cytokine activation processes in temporal artery cultures is an interesting approach for the better understanding of the physiopathology of GCA.


   Acknowledgments
 
We are grateful to Dr. Sharon Lynn Salhi for editorial assistance.

Received June 13, 2001

Accepted September 14, 2001


   References
Top
 Abstract
 Methods
 Results
 Discussion
 References
 

  1. Andersson R, Jonsson R, Tarkowski A, Bengtsson BA, Malmvall BE, 1987. T-cell subsets and expression of immunological activation markers in the arterial walls of patients with giant cell arteritis. Ann Rheum Dis. 46:915-923. [Abstract/Free Full Text]
  2. Andersson R, Hansson GK, Söderström T, et al. 1988. HLA-DR expression in the vascular lesion and circulating T lymphocytes of patients with giant cell arteritis. Clin Exp Immunol. 73:82-87. [Medline]
  3. Banks PM, Cohen MD, Ginsburg WW, 1983. Immunohistologic and cytochemical studies of temporal arteritis. Arthritis Rheum. 26:1201[Medline]
  4. Cid MC, Campo E, Ercilla G, et al. 1989. Immunohistochemical analysis of lymphoid and macrophage cell subsets and their immunologic activation markers in temporal arteritis. Arthritis Rheum. 32:884-893. [Medline]
  5. Wawrik SO, Ayberk H, Boyd AW, Rode J, 1991. Analysis of adhesion molecules in immunopathogenesis of giant cell arteritis. J Clin Pathol. 44:497-501. [Abstract/Free Full Text]
  6. Lavignac C, Jauberteau-Marchan MO, Liozon E, et al. 1996. Etude immunohistochimique des lésions d'artérite temporale de Horton avant et au cours de la corticothérapie. Rev Méd Interne. 17:814-820.
  7. Weyand CM, Hicok KC, Gene C, Hunder GG, Goronzy JJ, 1994. Tissue cytokine patterns in patients with polymyalgia rheumatica and giant cell arteritis. Ann Intern Med. 121:484-491. [Abstract/Free Full Text]
  8. Wagner AD, Goronzy JJ, Weyand CM, 1994. Functional profile of tissue infiltrating and circulating CD68+ cells in giant cell arteritis. Evidence for two components of the disease. J Clin Invest. 94:1134-1140.
  9. Roblot P, Morel F, Lelièvre E, et al. 1997. Serum cytokines and cytokine receptor levels in patients with giant cell arteritis during corticotherapy. J Rheumatol. 23:408-410.
  10. Roche NE, Fulbright JW, Wagner AD, et al. 1993. Correlation of interleukin-6 production and disease activity in polymyalgia rheumatica and giant cell arteritis. Arthritis Rheum. 36:1286-1294. [Medline]
  11. Lecron JC, Roblot P, Chevalier S, et al. 1993. High circulating leukemia inhibiting factor in patients with giant cell arteritis: independent regulation of LIF and IL-6 under corticotherapy. Clin Exp Immunol. 92:23-26. [Medline]
  12. Weyand CM, Fulbright JW, Hunder GG, Evans JM, Goronzy JJ, 2000. Treatment of giant cell arteritis: interleukin-6 as a biologic marker of disease activity. Arthritis Rheum. 43:1041-1048. [Medline]
  13. Neuhaus T, Totzke G, Gruenewald E, et al. 2000. Tumor necrosis factor-alpha gene expression and production in human umbilical arterial endothelial cells. Clin Sci (Colch). 98:461-470.
  14. Imai M, Goepfert C, Kaczmarek E, Robson SC, 2000. CD39 modulates IL-1 release from activated endothelial cells. Biochem Biophys Res Commun 270:272-278. [Medline]
  15. Clauss M, Sunderkotter C, Sveinbjornsson B, et al. 2001. A permissive role for tumor necrosis factor in vascular endothelial growth factor-induced vascular permeability. Blood. 97:1321-1329. [Abstract/Free Full Text]
  16. Belmin J, Bernard C, Corman B, et al. 1995. Increased production of tumor necrosis factor and interleukin-6 by arterial wall of aged rats. Am J Physiol. 268:H2288-H2293. [Abstract/Free Full Text]
  17. Fukai T, Siegfried MR, Ushio-Fukai M, Griendling KK, Harrison DG, 1999. Modulation of extracellular superoxide dismutase expression by angiotensin II and hypertension. Circ Res. 9: (85) 23-28.
  18. Bakker EN, Van Der Meulen ET, Spaan JA, Van Bavel E, 2000. Organoid culture of cannulated rat resistance arteries: effect of serum factors on vasoactivity and remodeling. Am J Physiol Heart Circ Physiol. 278:H1233-H1240. [Abstract/Free Full Text]
  19. Weyand CM, Tetzlaff N, Björsson J, et al. 1997. Disease patterns and tissue cytokine profiles in giant cell arteritis. Arthritis Rheum. 40:19-26. [Medline]
  20. Cid MC, Font C, Oristrell J, et al. 1998. Association between strong inflammatory response and low risk of developing visual loss and other cranial ischemic complications in giant cell (temporal) arteritis. Arthritis Rheum. 41:26-32. [Medline]
  21. Weyand CM, Hafner V, Kaiser M, Goronzy JJ, 1998. Giant cell arteritis—a molecular approach to the multiple facets of the syndrome. Ann Med Interne (Paris) 149:420-424. [Medline]
  22. Brack A, Martinez-Taboada V, Stanson A, Goronzy JJ, Weyand CM, 1999. Disease patterns in cranial and large-vessel giant cell arteritis. Arthritis Rheum. 42:311-317. [Medline]
  23. Kaiser M, Younge B, Bjornsson J, Goronzy JJ, Weyand CM, 1999. Formation of new vasa vasorum in vasculitis. Production of angiogenic cytokines by multinucleated giant cells. Am J Pathol. 155:765-774. [Abstract/Free Full Text]
  24. Szekanecz Z, Shah MR, Pearce WH, Koch AE, 1994. Human atherosclerotic abdominal aortic aneurysms produce interleukin (IL)-6 and interferon-gamma but not IL-2 and IL-4: the possible role for IL-6 and interferon-gamma in vascular inflammation. Agents Actions Suppl. 42:159-162.
  25. Frostegard J, Ulfgren AK, Nyberg P, et al. 1999. Cytokine expression in advanced human atherosclerotic plaques: dominance of pro-inflammatory (Th1) and macrophage-stimulating cytokines. Atherosclerosis. 145:33-43. [Medline]
  26. Libby P, Aikawa M, 1998. New insight into plaque stabilisation by lipid lowering. Drugs. 56:9-13.



This article has been cited by other articles:


Home page
 NEJMHome page
C. M. Weyand and J. J. Goronzy
Medium- and Large-Vessel Vasculitis
N. Engl. J. Med., July 10, 2003; 349(2): 160 - 169.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Blain, H.
Right arrow Articles by Jeandel, C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Blain, H.
Right arrow Articles by Jeandel, C.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
All GSA journals The Gerontologist
Journals of Gerontology Series B: Psychological Sciences and Social Sciences