Sarcopenia and cognitive impairment in elderly women: results from the EPIDOS cohort

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1 29. Mitnitski A, Fallah N, Rockwood K. Transitions in cognitive status in relation to frailty in older adults: a comparison of three frailty measures. J Nutr Health Aging 2011; 15: Raji MA, Al Snih S, Ostir GV et al. Cognitive status and future risk of frailty in older Mexican Americans. J Gerontol A Biol Sci Med Sci 2010; 65: Song X, Mitnitski A, Rockwood K. Nontraditional risk factors combine to predict Alzheimer disease and dementia. Neurology 2011; 77: Dasgupta M, Rolfson DB, Stolee P et al. Frailty is associated with postoperative complications in older adults with medical problems. Arch Gerontol Geriatr 2009; 48: Hilmer SN, Perera V, Mitchell S et al. The assessment of frailty in older people in acute care. Australas J Ageing 2009; 28: Fabrício-Wehbe SC, Schiaveto FV, Vendrusculo TR et al. Cross-cultural adaptation and validity of the Edmonton Frail Scale - EFS in a Brazilian elderly sample. Rev Lat Am Enfermagem 2009; 17: Rockwood K, Andrew M, Mitnitski A. A comparison of two approaches to measuring frailty in elderly people. J Gerontol A Biol Sci Med Sci 2007; 62: Buchman AS, Boyle PA, Wilson RS et al. Frailty is associated with incident Alzheimer s disease and cognitive decline in the elderly. Psychosom Med 2007; 69: Yassuda MS, Lopes A, Cachioni M et al. Frailty criteria and cognitive performance are related: data from the FIBRA study in Ermelino Matarazzo, São Paulo, Brazil. J Nutr Health Aging. 2012; 16: Davis DH, Rockwood MR, Mitnitski AB et al. Impairments in mobility and balance in relation to frailty. Arch Gerontol Geriatr 2011; 53: ADD: Ricou B, Merlani P. What limits for acute care in the elderly? Curr Opin Anaesthesiol 2008; 21: Received 2 December 2011; accepted in revised form 23 August 2012 Age and Ageing 2013; 42: The Author Published by Oxford University Press on behalf of the British Geriatrics Society. doi: /ageing/afs173 All rights reserved. For Permissions, please journals.permissions@oup.com Published electronically 7 December 2012 Sarcopenia and cognitive impairment in elderly women: results from the EPIDOS cohort GABOR ABELLAN VAN KAN 1,2*,MATTEO CESARI 1,2,SOPHIE GILLETTE-GUYONNET 1,2,CHARLOTTE DUPUY 1,2, FATI NOURHASHÉMI 1,2,ANNE-MARIE SCHOTT 3,OLIVIER BEAUCHET 4,CÉDRIC ANNWEILER 4,BRUNO VELLAS 1,2, YVES ROLLAND 1,2 1 Gérontopôle de Toulouse, Department of Geriatric Medicine, Toulouse University Hospital, 170, avenue de Casselardit, Toulouse 31059, France 2 INSERM Unit 1027, University Toulouse-III, Toulouse 31059, France 3 Department of Medical Information, Lyon University Hospital, Lyon 69000, France 4 Division of Geriatric Medicine, Department of Neuroscience, Angers University Hospital, Angers University Memory Center; UPRES EA 2646, University of Angers, UNAM, Angers 49933, France * Address correspondence to: G. Abellan van Kan. Tel: (+33) ; Fax: (+33) abellan-van-kan-g@chu-toulouse.fr Abstract Background: common pathophysiological pathways are shared between age-related body composition changes and cognitive impairment. Objective: evaluate whether current operative sarcopenia definitions are associated with cognition in community-dwelling older women. Design: cross-sectional analyses. Subjects: a total of 3,025 women aged 75 years and older. Measurements: body composition (assessed by dual energy X-ray absorptiometry) and cognition (measured by short portable mental status questionnaire) were obtained in all participants. Multivariate logistic regression models assessed the association of six operative definitions of sarcopenia with cognitive impairment. Gait speed (GS, measured over a 6-meter track at usual pace) and handgrip strength (HG, measured by a hand-held dynamometer) were considered additional factors of interest. 196

2 Sarcopenia and cognitive impairment in elderly women Results: a total of 492 (16.3%) women were cognitively impaired. The prevalence of sarcopenia ranged from 3.3 to 18.8%. No sarcopenia definition was associated with cognitive impairment after controlling for potential confounders. To proof consistency, the analyses were performed using GS and HG, two well-established predictors of cognitive impairment. Low GS [odds ratio (OR) 2.42, 95% confidence interval (CI) ] and low HG (OR: 1.81, 95% CI: ) were associated with cognitive impairment. Conclusion: no significant association was evidenced between different operative sarcopenia definitions and cognitive impairment. The study suggests that the association between physical performance and cognitive impairment in not mediated by sarcopenia. Keywords: sarcopenia, older adults, cognition, muscle mass, cognitive decline, community dwelling, women Introduction Recent reports have demonstrated the existence of a relationship between changes in age-related body composition parameters, cognition and brain atrophy in early Alzheimer s disease [1 3]. This has generated the hypothesis that changes in the fat mass or the lean mass may share underlying pathophysiological mechanisms with cognitive impairment. However, supporting data are still scarce and controversial, and the association of sarcopenia with cognition has never been specifically explored [4, 5]. Several studies evidence the presence of vitamin D receptors in both muscular cells and neurons, potentially explaining the cognitive consequences in the case of hormone deficiency [5, 6], and that pro-inflammatory cytokines are capable to alter the balance between synthesis and breakdown of muscle proteins representing a possible link among decreased muscle mass [7, 8], poor physical functioning [9] and cognitive impairment [8, 10]. It is well established that an increased fat mass and cognitive impairment present common mediators, such as leptin, an adipocytederived hormone [11 13], hyperinsulinaemia and higher levels of advanced glycation end products [14, 15], midlife obesity [16], as well as the low chronic pro-inflammatory state typical of older people [10, 17]. Finally, the beneficial effects of physical activity on the muscle mass, fat mass and strength seem to parallel similarly preventive actions on cognition, again by possibly influencing the insulin axis, vascular and neurotrophic factors, endorphins or inflammation [18]. From an initial definition of age-related muscle mass loss, sarcopenia has evolved to current operative definitions simultaneously capturing both quantitative (i.e. muscle mass) and qualitative (i.e. muscle strength and function) declines occurring to the ageing muscle [19, 20]. Although this bi-dimensional nature of sarcopenia is currently accepted by most working groups on sarcopenia, there is no unanimous agreement about the best definition to operatively measure sarcopenia in the clinical and research settings so that all definitions co-exist in scientific literature [21]. Gait speed (GS) and handgrip strength (HG) have both shown to be predictive of a wide range of critical health outcomes, including mortality, health care costs, disability and dementia [22 24]. Because GS and HG are relatively easy to obtain, these two variables are part of most operative definitions of sarcopenia in order to characterise the bi-dimensional nature of this phenomenon. The hypothesis, of the present paper, is that age-related skeletal muscle modifications might be related to cognitive impairment in older adults. Thus, cross-sectional analyses were performed to verify whether different operative definitions of sarcopenia are associated with cognitive performance in a large cohort of community-dwelling older women. Methods EPIDOS cohort Data are from the Epidemiologie de l Osteoporose (EPIDOS) cohort, a French observational prospective multi-centre cohort study designed to evaluate risk factors for hip fractures in community-dwelling women aged 75 years and older. Details about the study have previously been published [25]. Briefly, between January 1992 and January 1994, 7,598 women from five French cities volunteered to participate in EPIDOS. Women unable to walk independently (aids were allowed), with a history of femoral neck fracture or hip replacement, or were institutionalised were excluded. Local ethics committee of the participating centres approved the study, and each participant provided informed consent. Study sample The participants of two EPIDOS centres (Toulouse, n = 1,492; and Lyon, n = 1,563) were considered for the present analyses as these two centres specifically measured appendicular lean mass (ALM) on top of the main body composition parameters (lean mass, fat mass and bone mineral density) requested for the whole EPIDOS cohort. Assessment of covariates Participants underwent standardised visits, including administration of structured questionnaires, clinical examination and assessment of physical performance. Visits were conducted by trained nurses. Education was defined by a dichotomous 197

3 variable (i.e. graduate versus not). Dressing, toileting and mobility were assessed as basic activities of daily living (ADL) and categorised as a single dichotomous variable, independent or not, for all of the three items [26]. Type, frequency and duration of self-reported recreational activities (such as walking, gymnastics, cycling, swimming or gardening) were also recorded. The variable physically active was defined to approximately identify the fittest 20% of the study sample, that is equivalent at having practiced at least a 1-h activity or more per week over the past month [4]. Assessment of body composition parameters Body composition parameters were assessed using a dual energy X-ray absorptiometry (DXA) scanner (Lunar DPX-Plus, GE LUNAR Corp., Madison, WI). DXA measurements were performed by a trained technician, and the DXA machine was regularly calibrated. Lean mass, fat mass and ALM, measured in kilograms were obtained for each participant. Sarcopenia was operatively defined using six different approaches commonly used in literature (see Table 1): Definition by Baumgartner et al. [27]: assessed by ALM relative to height squared measured in meters (ALM h 2 ). Comparing the index values with a threshold from a younger reference population, sarcopenia was defined as ALM h kg m 2. Definition by Delmonico et al. [28]: the cut-off point ALM h kg m 2,defining the threshold of sarcopenia, was derived from the Health Aging and Body Composition study database using the lowest 20th sexspecific percentile. Definition by Newman et al. [29]: residuals were calculated from linear regression models predicting ALM from height and fat mass. The lowest 20th percentile of the gender-specific distribution of residuals was used as the cut-off point defining sarcopenia. Definition by two International Working Groups on Sarcopenia (IWGS): the cut-off point ALM h kg m 2, combined with a poor performance in GS (threshold established at 1.0 ms 1 ), defined sarcopenia [30, 31]. Definition by the Special Interest Group (SIG) on cachexia-anorexia: sarcopenia was defined by combining poor performance in GS, threshold established at 0.8 ms 1, and a cutpoint for ALM h 2 of 5.45 kg m 2 [32]. Definition proposed by the European Working Group on Sarcopenia in Older People (EWGSOP): The definition is based on the proposed algorithm to identify sarcopenia by the preliminary presence of low GS (threshold established at 0.8 ms 1 ) and/or low HG (lowest quartile of sample distribution). The existence of one of these two criteria leads to the evaluation of sarcopenia, defined by ALM h kg m 2 [33]. All six sarcopenia variables were dichotomised based on the sarcopenia thresholds found in the original papers. For the EWGSOP definition, no specific threshold for HG was proposed and as done in other surveys the lowest quartile of the sample distribution was used to identify low HG [24]. Cognitive impairment Cognitive impairment was measured using the Short Portable Mental Status Questionnaire (SPMSQ) [34]. The SPMSQ is a 10-item questionnaire, originally developed to detect the presence of cognitive impairment in epidemiological studies. The validated cut-off value defining normal cognitive functioning (and used in the present analyses) is a score equal to 8 or above [35]. Assessment of gait speed and handgrip strength Both measurements are needed in order to operationalise the current definitions of sarcopenia. The assessment of GS is systematically proposed as a measure of muscular Table 1. Sample characteristics according to operative sarcopenia definitions Sarcopenia definition Prevalence [n (%)] Age (years) mean ± SD SPMSQ (score 0 10) median, IQR... Study sample ± 3.9 9, 8 10 ALM h 2 Baumgartner and col. [29] ALM h kg m (9.4) ± 3.9 9, 8 10 ALM h 2 Delmonico and col. [30] ALM h kg m (18.8) ± 4.4 9, 8 10 Residuals Newman and col. [31] Linear regression of ALM by height 425 (14.1) ± 4.4 9, 8 10 adjusted for fat mass ALM h 2 +GSIWGS[32, 33] ALM h kg m 2 GS 1.0 ms (14.2) ± 3.9 9, 7 10 ALM h 2 + GS SIG [34] ALM h kg m 2 GS 0.8 ms 1 89 (3.3%) ± 4.0 9, 7 10 ALM h 2 + GS and/or HG EWGSOP [35] ALM h kg m 2 GS 0.8 ms 1 Lowest 25th HG 142 (5.2) ± 4.2 9, 8 10 Results are presented as mean ± standard deviation (SD), or median and inter-quartile range (IQR) if distribution not normal. ALM, appendicular lean mass (in kilograms, kg); h 2, squared height (in meters, m); ms 1, meters per second. SPMSQ, short portable mental status questionnaire; IWGS, International Working Group on Sarcopenia; SIG, Special Interest Group (SIG) on cachexia-anorexia; EWGSOP, European Working Group on Sarcopenia in Older People; GS, gait speed; HG, handgrip strength. 198

4 Sarcopenia and cognitive impairment in elderly women function, HG is proposed also by the EWGSOP as a measure to assess strength (see Table 1). A standardised assessment of GS was performed at baseline. Participants were asked to perform a 6-meter walk at their usual pace. Walking aids were allowed. Testing began when the command start was given by the assessor, and time (in s) required to complete the task was recorded. The faster of two walks was retained for the present analysis. Two dichotomised GS variables (measured in ms 1 ) were created based on the 1.0 and 0.8 ms 1 thresholds in order to identify slow walkers in the different operative sarcopenia definitions. As an independent variable, GS was analysed based on the binary cutpoint of 1 ms 1. HG was measured for the dominant hand with a hydraulic hand-held dynamometer (Martin Vigorimeter, Medizin Tecnik, Tuttlingen, Germany). The size of the grip was adjusted to make the participant feel comfortable. The participant stood upright with the arm vertical and the dynamometer close to the body. The maximal peak pressure expressed in Newton per square meter (nm 2 ) was recorded from a set of three contractions and used for the present analyses. The lowest quartile of HG was used to identify the low grip strength in the absence of a proposed cutpoint in the original paper. As an independent variable, HG was analysed in quartiles, comparing highest vs. lowest group [25]. Statistical analyses Data were analysed with STATA v11.0 (Stata Corp., College Station, TX, USA). Variables were compared according to the presence/absence of the outcomes of interest using Student s t-test or Chi-square statistics as appropriate. For each operative sarcopenia definition, a multivariate logistic regression analyses assessed the association of sarcopenia with the dichotomised SPSMQ score. The models were adjusted for age, education, ADL disability, physical activity and study centre. Results The main characteristics of the study participants are presented in Table 1. The prevalence of sarcopenia ranged from 3.3 to 18.8% according to the different adopted operative definitions. Characteristics of the participants according to their SPMSQ score are shown in Table 2. Of 3,025 women, 492 (16.3%) had cognitive impairment. A significant difference Table 2. Characteristics according to the presence of cognitive impairment (n = 3,025) Variables, n (%) SPMSQ score <8 a (n = 492) SPMSQ score 8 a (n = 2,533)... Age <80 years 200 (40.6) 1,360 (53.7) < years 292 (59.4) 1,173 (46.3) Certificate of graduation Graduate 320 (65.3) 2,110 (83.4) <0.01 Less than graduate 170 (34.7) 421 (16.6) ADL disability Not disabled 356 (75.9) 1,795 (71.1) 0.03 Disabled 113 (24.1) 731 (28.9) Physically active Yes 102 (20.9) 723 (28.6) <0.01 No 387 (79.1) 1,808 (71.4) Gait speed (ms 1 ) >1ms 1 43 (9.1) 570 (22.7) <0.01 1ms (90.9) 1,945 (77.3) Hand grip strength (nm 2 ) (in quartiles) nm 2 81 (16.8) 657 (26.1) < nm 2 94 (28.1) 634 (25.2) nm (19.5) 639 (25.4) nm (35.5) 587 (23.3) Baumgartner and col. (ALM h kg m 2 ) No 374 (89.7) 2,068 (89.6) 0.95 Yes 43 (10.3) 240 (10.4) Delmonico and col. (ALM h kg m 2 ) No 344 (82.5) 1,870 (81.0) 0.48 Yes 73 (17.5) 438 (19.0) Newman and col. (lowest 20th residuals) No 353 (84.9) 1,945 (84.3) 0.77 Yes 63 (15.1) 362 (15.7) IWGS (ALM h kg m 2 + GS <1.0 ms 1 ) No 355 (84.7) 2,006 (86.0) 0.48 Yes 64 (15.3) 326 (14.0) SIG (ALM h kg m 2 + GS <0.8 ms 1 ) No 386 (94.6) 2,228 ( 97.1) 0.01 Yes 22 (5.4) 67 (2.9) EWGSOP (ALM h kg m 2 + GS and/or HG) No 389 (93.3) 2,191 (95.1) 0.14 Yes 28 (6.7) 114 (4.9) SPMSQ, short portable mental status questionnaire (scores 0 10); ADL, activities of daily living (dressing, toileting and mobility); GS, gait speed; HG, handgrip strength; ms 1, meters per second; nm 2, Newton per squared meter; ALM, appendicular lean mass (in kilograms, kg); h 2, for squared height (in meters, m); IWGS, International Working Group on Sarcopenia; SIG, Special Interest Group on cachexia-anorexia; EWGSOP, European Working Group on Sarcopenia in Older People. a Results are presented as number (percentage) or mean ± standard deviation. b Based on Student s t-test or Chi-square statistics as appropriate. P-value b 199

5 Table 3. Association of sarcopenia definitions with cognitive impairment Logistic regression models Included participants in nested models Crude model OR (95% CI) Adjusted model OR ( 95% CI) a... Model 1 Baumgartner and col. (ALM h 2 ) 2, ( ) 1.05 ( ) Model 2 Delmonico and col. (ALM h 2 ) 2, ( ) 0.97 ( ) Model 3 Newman and col. (Lowest 20th residuals) 2, ( ) 1.02 ( ) Model 4 IWGS (ALM h 2 + GS) 2, ( ) 1.11 ( ) Model 5 SIG (ALM h 2 + GS) 2, ( ) 1.48 ( ) Model 6 EWGSOP (ALM h 2 + GS and/or HG) 2, ( ) 1.18 ( ) OR, odds ratio; 95% CI, 95% confidence interval; ALM h 2, appendicular lean mass divided by height squared; IWGS, International Working Group on Sarcopenia; SIG, Special Interest Group (SIG) on cachexia-anorexia; EWGSOP, European Working Group on Sarcopenia in Older People; GS, gait speed; HG, handgrip strength. a Adjusted for age, certificate of graduation, ADL disability, physical activity and recruitment centre (Lyon-Toulouse). was found for most of the studied variables (i.e. age, education, ADL disability, physical activity, GS, HG and one of the sarcopenia definitions) across cognitive function groups. Results from unadjusted and adjusted regression models are presented in Table 3. Only one of the sarcopenia definitions (i.e. ALM h kg m 2 +GS 0.8 ms 1 ) was associated with cognition in crude analyses [odds ratio (OR), 1.89; 95% confidence interval (CI): ], but lost its statistical significance after inclusion of potential confounders in the model. In the adjusted models, no statistical association could be evidenced between cognitive impairment and the different sarcopenia operative definitions. To verify that the non-association was not due to specific peculiarities of our sample population or due to the statistical approach, we performed additional models using as independent variables of interest GS and HG (two well-established predictors of cognitive impairment at older age). Both low GS (OR: 2.42; 95% CI: ) and low HG (OR: 1.81; 95% CI: ) were significantly associated with cognitive function, suggesting that the results for sarcopenia in the EPIDOS study are consistent. Discussion In the present analyses, no association could be found between the different operative definitions of sarcopenia and cognitive impairment after adjustment for potential confounders. These findings were indirectly confirmed by the significant and independent association of GS and HG with cognition. The results are consistent with available evidence in dementia-free community-dwelling older adults, where low GS and low HG have proved to be strong risk factor for incident dementia in multiple surveys [22, 23]. The originality of the present study relies on the evaluation of cognition in relationship with several currently available sarcopenia definitions. To assess different operative sarcopenia definitions, simultaneously and in a same population, has to date never been explored. Although common underlying pathophysiological mechanisms have been hypothesised, the present analyses do not support a link between sarcopenia and cognitive impairment. To the authors knowledge, no study has specifically been performed on sarcopenia (evaluated by ALM), thus only scarce evidence exists to better appreciate the present results. Three cross-sectional articles were retrieved assessing the association between body composition parameters and cognition. In these surveys, no specific approach was used to assess sarcopenia, and findings were based on the total lean mass (including the abdominal visceral lean mass) rather than ALM. An association between cognitive impairment and low lean mass was previously found in 7,105 women of the French EPIDOS cohort [2], this finding was only partially confirmed in a recent Chinese study where only men showed a significant relationship [3]. The discordance of EPIDOS results is mainly due to the body composition approach of each article. Nourhashemi et al. used a non-adjusted-for-height crude value of the total lean mass, whereas the present article assessed specifically a heightadjusted muscle mass by the means of measuring ALM. Of interest is an article assessing cognition, lean mass and fat mass (with impedance analysis) in 4,000 geriatric hospital patients [5]. The fat mass was associated (but not lean mass) with moderate and severe cognitive impairment, but not with mild impairment. These results suggest an association with body composition at later stages of cognitive impairment. Only one longitudinal case control study with cognitive impairment assessed 7 years later has been found in literature, also from the EPIDOS cohort. In this survey, lean and fat mass were not found to be associated factors with an increased risk of dementia [4]. It is possible, like for other critical health outcomes, that only the performance or strength measures, but not the muscle mass parameters, are associated with cognition [36, 37]. 200

6 Sarcopenia and cognitive impairment in elderly women The SIG sarcopenia definition was close to statistical significance in multivariate analysis with an OR of 1.48 (95% CI: ). This definition used the lowest ALM h 2 and the lowest GS thresholds in between the different sarcopenia definitions, and so identifying the most severe sarcopenic population among participants. Other than evoking a lack of statistical power to justify this result [as only 89 (3.3%) participants presented sarcopenia by this definition], it could also be possible that skeletal muscle health may still predict cognitive impairment beyond a certain threshold of decline. Nevertheless, this weak association of sarcopenia with cognitive impairment may simply be driven by the inclusion in its definition of physical performance and strength parameters. Consequently, the increased risk is purely due to the additional qualitative components rather than to the skeletal muscle quantity. This issue (consistent with available evidence) may still need further investigation with specifically designed studies. Another hypothesis suggested by the results of a recent survey (and needing further inquiry) is that sarcopenia could be associated with cognition at the dementia-stage, with the possibility that no changes in body composition occur at the early stage of cognitive impairment [5]. Although the present analyses suggest that sarcopenia is not a risk factor for dementia, body composition parameters could still be prognostic factors for worsening cognitive impairment at a dementia-stage. Finally, five of the six sarcopenia definitions are based on specific cut-offs obtained from American cohorts. Although there is a general assumption that these cut-offs are very similar for a European population, no specific surveys have been performed assessing this issue. Eventually different cut-offs for an operational definitions of sarcopenia based on European data could change the present non-association. The generalisability of the results is challenged by the restriction of the EPIDOS study to only relatively healthy older women; therefore, our findings might not be applicable to men, different settings and other health profiles. The cross-sectional design of the present analyses does not allow us to evaluate any cause effect relationship in the studied association. Finally, we cannot exclude the presence of third factors differently explaining our results. These limitations could dampen the association between cognition and sarcopenia. Moreover, the dynamic nature of body composition parameters could challenge the actual results as changes in ALM over time, evoked as a possible sarcopenia definition rather than a single-point assessment, could be associated with cognitive impairment [38]. Only repeated DXA assessment and longitudinal analysis might solve this issue. Cognitive function was assessed by the SPMSQ. This instrument, although commonly administered in epidemiological surveys, is a screening tool and not accurate as a clinical comprehensive assessment of cognitive function. Even more, in this cohort of cognitive well-functioning elderly women, the use of the SPMSQ could have weakened the association between cognitive impairment and sarcopenia. Presumably, the use of more sensible cognitive tests for slightly impaired populations would have been more adapted. Finally, statistical power needs to be addressed to justify the non-association. No specific analyses have been performed, but it seems unlikely that the study was underpowered given the large sample size and the associations obtained for GS and HG. Conclusions In this cohort of community-dwelling independent older women, different operative sarcopenia definitions were not found to be associated with cognitive impairment after adjustment for potential confounders. Differently, low GS and low HG confirmed to be associated with cognitive impairment. The analyses suggest that more severe stages of sarcopenia (severe impairments in mass and function) could be associated with cognitive impairment. Further studies on the topic are needed to confirm these findings, including other samples like severe sarcopenic patients or participants with cognitive impairment at a dementia-stage. Acknowledgements Investigators of the EPIDOS (EPIdemiologie de I OSteoporose) study. Coordinators: Breart, Dargent-Molina, Meunier, Schott, Hans, Delmas. Principal Investigators (centre): Baudouin, Sebert (Amiens); Chapuy, Schott (Lyon); Favier, Marcelli (Montpellier); Haussherr, Menkes, Cormier (Paris); Grandjean, Ribot (Toulouse). 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