Characteristics of Alzheimer’s Disease Patients with Severe Executive Disorders

Abstract

Background:

Executive dysfunctions in Alzheimer’s disease (AD) have been assessed using variable batteries and/or in selected populations.

Objective:

The primary objective of this observational study was to determine the prevalence and severity of executive dysfunction in AD patients using a previously validated battery. The secondary objective was to determine the characteristics including treatment outcomes of AD patients with severe executive dysfunction.

Methods:

The study included AD patients with mild-to-moderate dementia aged 60 or over, consulting in various clinical settings including memory clinics and requiring the introduction of an antidementia drug. Executive dysfunction was examined using a validated, shortened executive battery.

Results:

381 patients were included. Executive dysfunctions were observed in 88.2% of the patients (95% CI: 84.9–91.4) and were severe (defined as ≥2/3 impaired scores) in 80.4% (95% CI: 76.9–84.8). Global hypoactivity with apathy was more frequent (p = 0.0001) than impairment in executive function tests. The 308 patients with severe executive dysfunction were older (p = 0.003) and had more severe dementia (p = 0.0001). Similarly, in the subset of 257 patients with mild dementia, individuals with severe executive dysfunction were older (p = 0.003) and had more severe dementia. Global hypoactivity was independently associated with difficulties in IADL and a higher caregiver burden (p = 0.0001 for both). The severity of executive dysfunction did not significantly influence the patients’ outcomes at 6 months.

Conclusions:

Executive dysfunction is a very common disorder in a representative population of patients with mild-to-moderate AD. It was independently correlated with impaired autonomy and increased caregiver burden but did not significantly influence treatment outcomes.

Keywords

Alzheimer’s disease apathy cognitive disorders control function executive function treatment

INTRODUCTION

Executive dysfunction is frequent in Alzheimer’s disease (AD) with mild-to-moderate dementia [1, 2].The profile of cognitive and behavioral executive dysfunctions has been recently characterized in mild and moderate AD [3] by the application of (i) a systematic cognitive and behavioral battery and (ii) validated diagnostic criteria [4]. Executive function is an umbrella term referring to a wide range of high-level cognitive abilities and it has been used with various meanings. Following our previous validation study [4], we use the terminology of executive disorders to refer to impairment of control functions both in the cognitive (i.e., assessed using tests) and behavioral (i.e., assessed using inventory) domains. Cognitive impairment markedly affected word generation, planning and shifting under time constraints (measured using the Trail Making Test B), whereas the behavioral disorder was predominantly associated with apathy and a reduction in activity [3]; these findings are in good agreement with the results of studies that separately examined specific executive functions [5 –13]. These behavioral and cognitive dysexecutive disorders observed in AD patients with amnesia at the forefront of the clinical picture should be differentiated from the frontal variant of AD [14]. This behavioral-dysexecutive variant of AD refers to patients with AD (verified by neuropathological examination or at least typical abnormalities of CSF biomarkers) with prominent or exclusive behavioral (i.e., frontotemporal dementia like presentation) or cognitive dysexecutivedisorders [15].

The prevalence and severity of dysexecutive disorders in AD remains to be established in a population representative of clinical practice. This objective is facilitated by the recent validation of a shortened battery assessing executive dysfunctions in AD that provides essentially the same diagnostic accuracy as a comprehensive battery in a crossed validation study [16]. The shortened battery reduces the duration of cognitive assessment, reduces the proportion of missing data, and thus facilitates the determination of the prevalence of executive impairment in AD population representative of clinical practice. Furthermore, the characteristics and treatment outcomes associated with AD patients with marked executive dysfunction have not yet been studied in detail. Hence, the present study was designed to address these issues; we deliberately included AD patients from various types of memory center and screened them for executive impairment using a shortenedbattery.

The primary objective of this observational study was to determine the prevalence and severity of executive dysfunctions in patients with mild-to-moderate AD. The secondary objective was to determine (1) the characteristics, (2) the relationship with difficulties in Instrumental Activities of Daily Living (IADL) and caregiver burden and (3) treatment outcomes of AD patients according to the severity of executive dysfunction.

METHODS

Population

Patients ≥60 years referred in participating neurologists, geriatricians and psychiatrists (n = 137) and academic memory clinics (n = 15) for Alzheimer’s disease according to McKhann criteria [17] in whom the introduction of de novo antidementia drug was indicated according to French guidelines [18] were eligible (Fig.1). Inclusion criteria were: French version [19] of the Mini Mental State Examination (MMSE) [20] score ≥15/30, available informant, and follow-up at the 24 weeks (±4 weeks) visit as recommended by French guidelines [18]. Patients with contraindication to antidementia drug and lack of informed consent were excluded. The choice of antidementia drug (donepezil, rivastigmine, galantamine and memantine) was decided by the investigator according to recommendations except that at least one of 3 patients of each center should receive a different treatment than the other ones. The study has been approved by institutional review board.

Four hundred thirty seven patients (Fig. 1) were eligible and 381 (follow-up population) of them fitted inclusion criteria. Their characteristics (Table 1) did not differ according to type of center except for education (higher in academic memory clinic), and for choice of treatment (with lower prescription of memantine in academic memory clinic). Among the included population, 283 patients (per-protocol population) were receiving treatment at an effective dose (donepezil and transdermal rivastigmine: All dosages; oral rivastigmine >4.5 mg daily; galantamine: >8 mg daily; memantine >15 mg daily) at the follow-up visit.

Assessment

The investigators performing dementia assessments at the memory clinics were not blinded to the patients’ treatment status. The severity of dementia was rated according to their MMSE, difficulties in IADL were rated on the 4 IADL scale [21] used in the Paquid study [22], the caregiver burden was scored using a shortened version of the French adaptation [23] of the Zarit scale [24]), and treatment outcome was assessed with the Clinical Global Impression of Change (CGI-C) [25]. A shortened assessment of executive function was performed by applying the profile of executive dysfunctions in AD determined by the GREFEX study [3], which has been recently validated [16] and can be administered by all types of healthcare structures. It includes the scores from two tests (categorical fluency and the Trail Making Test part B) and mean scores from three domains of the Behavioral Dysexecutive Syndrome Inventory (hypoactivity with apathy-abulia; difficulties in anticipation and initiation of activities; disinterest and indifference to the patient’s own concern and others, which are collectively referred to here as “global hypoactivity”) (see Supplementary Material). In university hospital memory clinics, the executive assessment was performed by a neuropsychologist. In addition to the short executive assessment, patients underwent three tests in which performance is frequently impaired for AD patients (the full Trail Making Test, the Stroop test and Six Elements test), together with the full Behavioral Dysexecutive Syndrome Inventory assessing the 12 dysexecutive domains (as detailed in the Supplementary Material). Lastly, the brief informant form of the Neuropsychiatric Inventory [26], a confrontation naming test and the investigating center’s usual standardized depression scale were administered [27].

Criteria of dysexecutive disorders on the shortened battery

According to a previously validated method [16, 28], the standardized residuals (z scores) of the global hypoactivity score from the Behavioral Dysexecutive Syndrome Inventory, the error score in the Trail Making Test B and categorical fluency were computed using the full set of 780 controls in the GREFEX study [4]. Performance analysis was based on a validated framework for the interpretation of cognitive data, which had previously been found to provide the best diagnostic accuracy [28]. Briefly, standardized residuals (i.e. z scores for the transformed scores from the neuropsychological tests and inventory) were calculated using significant demographic factors (age, educational level and gender). The z score of the global hypoactivity, the z score for the error score in the Trail Making Test B and the z score from the fluency test were dichotomized (normal vs. impaired) using the 5th percentile values calculated in a normalization sample [4]. Threshold expressed in percentile was shown to control more accurately for false positive than the usual use of threshold expressed as standard deviation below the control mean [28]. The composite score for executive function was the average of the z scores for global hypoactivity, the Trail Making Test B error and categorical fluency. Executive dysfunction was considered to be present when the composite score for executive function was below the cutoff. On the basis of the results of the GREFEX, severe executive dysfunction was defined as an impairment of at least two out of the three z scores (global hypoactivity, Trail Making Test B errors and categorical fluency) [3, 4]. This corresponded to the lower quartile: ≥2/3 scores were impaired in 1% of controls, in 24.8% of all patients and in 21% of patients with a disease differing fromAD [3, 4].

Statistics

Data quality control

Systematic quality control revealed atypical performance measured at the initial assessment in seven patients included by three primary care centers. Thus, all analyses were checked after exclusion of the 9 patients included by the three centers (three patients per center). These analyses provided exactly the same results and so are not detailed here.

Characteristics of AD

The frequency of impairment of executive disorders and of severe executive disorders were computed as well as their 95% Confidence Interval (CI) using the formula: $p \pm z \times \sqrt{(p \times (1 - p) / n)}$ . Characteristics at initial visit (age, gender, education, MMSE, dementia severity, IADL, Mini-Zarit and treatment) were compared as a function of the severity of dysexecutive disorders (non-severe,severe).

Relationship between instrumental activities of daily living, caregiver burden and neuropsychological disorders

The determinants of difficulties in IADL and the caregiver burden were analyzed in two series of stepwise linear regressions (one for the IADL score and the other for Mini-Zarit score). The following variables were fed into the regression: Age, gender, educational level, the z score for the MMSE, the z score for global hypoactivity, the z score for errors in the Trail Making Test B and the z score for the fluencytest).

Outcome according to the severity of dysexecutive disorders

Outcome at 6 months was assessed using the CGI-C and the difference between the initial and 24-week scores for the MMSE, IADL scale and Mini-Zarit. They were compared according to the severity of executive dysfunctions (non-severe, severe). The relationship between severity of executive disorders and outcome was also analyzed directly (i.e., independently of the criterion of severe dysexecutive disorders): The composite executive score was compared (t test) according to outcome determined using the CGI-C and we also examined the correlation (Pearson test) between the composite executive score and the difference between the initial and 24-week scores for the MMSE, IADL scale andMini-Zarit.

Analyses of the follow-up population were performed using a t test (for continuous variables) or a chi² test with continuity correction (for other variables). All analyses were repeated after exclusion of the nine patients from the three centers with atypical performance. Furthermore, this outcome was analyzed in the per-protocol population (n = 283, the patients having taken their treatment at an effective dosage until the 6 months visit. The threshold for statistical significance was set to p≤0.05, unless otherwise indicated. Statistical analyses were performed using SAS software (SAS Institute Inc.,Cary, NC).

Results

Frequency of severe and non severe executive dysfunction

Executive dysfunctions were observed in 336 (88.2%; 95% CI: 84.9–91.4) and were severe in 308 (80.4%; 95% CI: 76.9–84.8) patients. The impairment of the 3 scores was observed in 175 patients (45.9%). Z scores of the 3 executive tests and the composite executive score are presented in Table 2 according to the number of impaired scores. Global hypoactivity (n = 328) was more frequent than impairment of verbal fluency (n = 259) and poor performance in the Trail Making Test B (n = 267) (McNemar test: p = 0.0001, both). There was no significant difference between the frequencies of verbal fluency and poor performance in the Trail Making Test B (p = 0.2).

Characteristics of AD patients according to severity of executive dysfunction

The 308 patients with severe executive dysfunctions (Table 3) were older and had more severe dementia (as shown by a lower MMSE score, greater difficulties in IADL and a greater caregiver burden) than patients with non-severe executive dysfunctions. A similar analysis was performed for the 257 patients with mild dementia (defined as an MMSE score ≥20) and yielded similar results: The 191 patients with severe executive dysfunction were older than patients with no executive dysfunction or non-severe executive dysfunction (mean±SD age: 79.9±6.1 versus 77.1±6.4, respectively; p = 0.002) and had more severe dementia, as evidenced by a lower MMSE score (22.6±2.2 versus 23.9±2.2, respectively; p = 0.0001), greater difficulties in IADL (8.63±2.73 versus 6.48±2.44, respectively; p = 0.0001) and a greater caregiver burden (2.73±1.71 versus 1.98±1.58, respectively;p = 0.03).

Relationship between the IADL score, caregiver burden and neuropsychological disorders

With regard to IADL, the stepwise linear regression selected (1) the z score for global hypoactivity (R² = 0.356; p = 0.0001), (2) age (R² = 0.045; p = 0.0001) and (3) the z score for the MMSE (R² = 0.025; p = 0.0001). With regard to the caregiver burden (the mini- Zarit score), the z score of the global hypoactivity (R² = 0.263; p = 0.0001) was the only factor selected.

Outcome analyses

According to the CGI-C, 260 (68.2%) patients improved or were stable after 24 weeks (Table 4). None of the outcome measures was significantly influenced by the severity of executive dysfunctions, other than a non-significant trend towards more deterioration in the group with severe executive dysfunctions. An analysis restricted to the per-protocol population and an analysis after exclusion of the nine above-mentioned patients yielded exactly the same results (data not shown).

Using the composite executive score, the sole significant analysis concerned the deterioration on CGI-C which was associated with more severe executive score at baseline (deterioration: –7.439±4.95; no deterioration: –6.389±4.62; p = 0.045) (correlation between the executive score and difference between the initial and 24-week scores for the MMSE, IADL scale and Mini-Zarit: R = 0.03, R = –0.03, R = –0.07, respectively; p > 0.2, all).

An analysis (using the shortened battery) of the neuropsychological outcome (Table 5) showed that most scores worsened at the follow-up examination with the exception of global hypoactivity, which was stable.

Discussion

The present results reveal the very high prevalence of executive dysfunctions (88.2%; 95% CI: 84.9–91.4) and severe executive dysfunction (80.4%; 95% CI: 76.9–84.8%) in mild-to-moderate AD. The results also showed that patients with severe executive dysfunctions are older and are characterized by more severe dementia (as evidenced by the MMSE and IADL scores) and a higher caregiver burden as reflected by the Mini-Zarit score. This relationship was also observed in patients with mild dementia. The severity of executive dysfunction was not correlated with the treatment outcome. However, difficulties in IADL depended on the severity of behavioral executive dysfunctions, MMSE and age. Lastly, the caregiver burden was related to the severity of behavioral executive dysfunctions.

The present study adds to the existing knowledge in this field because it reveals the very high prevalence of executive dysfunctions in mild-to-moderate AD patients treated in real clinical practice. Importantly, executive impairment is a very common impairment - even in mild AD. Furthermore, the results confirm our previous report in which behavioral disorders were more frequent than executive cognitive impairment [3]; this finding suggests that the assessment of executive function should always include a validated behavioral inventory. Behavioral disorders are characterized by hypoactivity with loss of initiation and anticipation of action, withdrawal and disinterest - symptoms that are usually classified under the term “apathy”. It thus appears that apathy is observed in most AD patients - even those with mild dementia only. Accordingly, this behavioral disorder did not worsen at the 6-month visit. The observed frequency of impairment of categorical verbal fluency and performance in the Trail Making Test B is in line with previous reports [1 –3]. From a clinical point of view, our present results indicate that executive dysfunction is usual in AD and so cannot be considered as the hallmark of other type of dementia such as frontotemporal degeneration [29], Lewy body disease [30] and vascular cognitive impairment [31]. An important characteristic of typical AD profile lies in the earlier and more severe impairment of episodic memory than executive disorders [32, 15]. This neuropsychological profile contrasts with that of the behavioral-dysexecutive variant AD which is characterized by exclusive behavioral (i.e., frontotemporal dementia like presentation) or prominent cognitive dysexecutive disorders (defined by executive score 1 SD lower than that of memoryscore) [15].

The present study describes the features of AD patients with severe executive dysfunctions. Firstly, executive dysfunction was more severe in patients with severe dementia (as judged by the MMSE score). Although the MMSE does not assess executive function per se, we cannot rule out the possibility that severe executive dysfunction worsens overall cognitive performance. AD patients with severe executive dysfunction had greater difficulties in IADL and a greater caregiver burden (due to behavioral impairments). This situation was also observed in patients with mild AD. Finally behavioral executive dysfunction was an independent factor associated with impaired autonomy and a greater caregiver burden –regardless of the severity of the overall cognitive impairment (as reflected by the MMSE score). This finding supports the previously reported relationship between the severity of executive dysfunctions and difficulties in IADL in community-dwelling elderly people [33] and AD [34 –36] and indicates that the severity of executive dysfunctions is independently associated with difficulties in complex ADL and the intensity of the caregiver burden.

In contrast, the severity of executive dysfunction was not associated with the treatment outcome. The present study was not designed to examine the effect of treatment class on the relationship between executive dysfunction and outcome. Indeed, few detailed studies of treatment outcomes in AD have demonstrated a beneficial effect on neuropsychological parameters related to executive function. Better completion times in executive tests have been reported in patients treated with acetylcholinesterase inhibitors [37 –39]. It remains to be established whether this gain in speed is related to an improvement in attention-executive control or in sensorimotor processes [11]. In the present study, we found that global hypoactivity with apathy did not worsen between the initial visit and the follow-up visit. The effect of acetylcholinesterase inhibitor on behavioral measures remains controversial in placebo-controlled studies [40 –43], although a Cochrane meta-analysis has shown that acetylcholinesterase inhibitors are associated with benefit for behavioral measures [44]. There is only one acetylcholinesterase study which has demonstrated benefit for depression/dysphoria, anxiety and apathy [40]. Although a pooled analysis of two memantine trials showed a slower worsening of behavior, the beneficial effect concerned agitation/aggression and not apathy [45].

Determination of factors associated with the severity of executive dysfunction was outside the scope of the present study. Considering the high frequency of severe executive dysfunction in patients with mild dementia, it seems unlikely that executive dysfunction can be attributed to the more widespread presence of neurofibrillary tangles. However, in moderate-to-severe dementia, extension of neurofibrillary tangles might have a role - as suggested by the poor executive performance observed in AD patients with high cerebrospinal fluid levels of Tau protein [46]. Although the influence of associated vascular lesions has been shown in an autopsy study [32], this parameters is modulated by the nature of the cognitive assessment and the severity of dementia [32, 47]. The older age in patients with severe executive dysfunction may be due to the high frequency of associated vascular lesion and Lewy body in older AD patients [48].The small size of early onset dementia prevented from further analyses in this specific group.

This study had several limitations. Its shortened battery did not include the Six Element test (despite the latter’s known, high sensitivity to mild AD) because the present population also included patients with moderate AD (who are usually unable to perform this test) [3]. As the present study focused on AD, its objective was not to examine the executive profile of other causes of dementia. This study was based on clinical criteria of AD without biomarker analyses. Thus it is likely that some patients with non-AD dementia have been included and this may have increased our estimation of severe executive dysfunction in AD. The absence of randomization and blinded assessments prevented us from analyzing the effect of drug classes on outcome. However, the main strength of this study lies in its estimation of the prevalence of executive dysfunction using a validated protocol and in a population of patients with mild-to-moderate AD, i.e., representative of clinical practice in a variety of healthcare structures.

RELATIONSHIP BETWEEN SPONSOR AND DATA MANAGEMENT AND ANALYSIS OF THE REFLEX STUDY

The trial was sponsored by Novartis; data were collected by ICTA (Dijon, France) which provided site monitoring throughout the study. The steering committee (OG, SB, MV, JPDM) developed the study protocol with the sponsor (JJP) and takes responsibility for the data and data analyses. The statistical analysis was performed by the first author and the sponsor had no role in data collection, data analysis and data interpretation. The corresponding author had full access to all the data in the study.

Footnotes

ACKNOWLEDGMENTS

Authors’ disclosures available online ().

Appendix

REFLEX Study Group: The following centers and investigators participated in this study (N = number of patients included at each center; investigators): Agen Cabinet Medical (N = 8; Larrieu JL), Altkirch Cabinet Medical (N = 9; Kubler C), Amiens University Hospital (N = 3; Devendeville A, Godefroy O), Amilly Centre Hospitalier (N = 2; Filippi M), Angers University Hospital (N = 6; Bouyx-Etcharry F), Arcachon Cabinet Medical (N = 3; Gaida P), Aulnay Sous Bois Hopital Robert Ballanger (N = 3; Abdulnayef A), Avignon Centre Hospitalier Henri Duffaut (N = 15; Nachar H), Bar le Duc Centre Hospitalier Jeanne D Arc (N = 1; Benoit C), Bastia Cabinet Medical (N = 3; Galletti P), Bavilliers Association Hospitaliere de Franche-Comte (N = 3; STEHLIN P), Bayonne Regional Hospital (N = 3; Ballan G), Belfort Cabinet Medical (N = 3; Malkoun I), Bergerac Cabinet Medical (N = 3; Delabrousse Mayoux JP), Biarritz Polyclinique D’aguilera (N = 2; Chanel Soulier MP), Bois Guillaume Clinique du Cedre (N = 3; Augustin J), Bordeaux Cabinet Medical (N = 3; Rigal B), Bourg en Bresse EHPAD Emile Pelicand (N = 8; Boge T), Bourgoin Jallieu Centre Hospitalier Pierre Oudot (N = 3; Balasoiu R), Brest University Hospital (N = 6; Gentric A), Brive SCP- Lubeau-Chazot (N = 3; Lubeau M), Bry Sur Marne Centre Hospitaliers les Murets (N = 3; Haddad V), Caen Cabinet Medical (N = 1; Fromager G), Caen Cabinet Medical (N = 3; Kerouanton A), Castres Hopital du Pays D’Autan (N = 3; Cufi MN), Cergy Cabinet Medical (N = 3; Dussaux P), Chateaubriant Pole Sante de Centre Hospitalier Oisel (N = 3; Doury E), Chatellerault Cabinet Medical (N = 3; ZAI L), Chaumont Cabinet Medical (N = 3; Saad S), Cholet Centre Hospitalier (N = 6; Delamarre Damier F), Clermont-Ferrand University Hospital (N = 9; Deffond D), Colmar Hopitaux Civils de Colmar (N = 3; Michel J), Corbie Centre Hospitalier (N = 3; Dami M), Eaubonne Hopital Simone Veil Eaubonne (N = 1; Mousnier Lompre A), Epinay sur Orge Cabinet Medical (N = 3; Le Fevre G), Etampes Centre Hospitalier (N = 2; Rahioui Sidki L), Etampes Centre Long Sejour (N = 3; Benhabib Benelhadj H), Grenoble University Hospital (N = 2; Moreaud O), Hazebrouck Ehpad Clos des Tilleuls (N = 3; Liagre A), Ivry Sur Seine Centre Hospitalier Charles Foix (N = 1; Kinugawa Bourron K), Juvisy Sur Orge Centre Hospitalier (N = 3; Berrani D), La Rochelle Cabinet Medical (N = 3; Gire Couret P), La Rochelle Hopital Saint Louis (N = 6; Anguenot A), La Seyne Sur Mer Espace Sante 2 (N = 6; Trefouret S), La Teste De Buch Centre Hospitalier Jean Hameau (N = 6; Gaida Rostane T), Lagardelle Sur Leze Clinique de Lagardelle (N = 2; Jammes JF), Lavaur Centre Hospitalier (N = 6; Desclaux F), Le Cateau Cambresis Centre Hospitalier (N = 3; Abied R), Le Lamentin Centre Hospitalier du Lamentin (N = 6; Chatot-Henry C), Lens Centre Hospitalier Dr Schaffner (N = 2; Senechal O), Les Essarts Cabinet Medical Asclepios (N = 2; Pujol JF), Lille EHPAD les Bateliers (N = 3; Huvent Grelle D), Limeil Brevannes Hopital Emile Roux (N = 9; David JP), Loos Groupe Hospitalier (N = 3; Chekroud H), Lyon Centre Hospitaliers Saint Jean de Dieu (N = 3; Gallice I), Marseille Centre Gerontologique DPTAL (N = 3; Rochefort N), Marseille Cabinet Médical (N = 6; Denis B), Mirecourt Centre Hospitalier (N = 2; Paquot Chaudron C), Montauban Clinique du Pont de Chaume (N = 3; Angibaud G), Montluçon Centre Hospitalier (N = 5; Maillet Vioud M), Moyeuvre Grande Hopital Saint Maurice (N = 4; Cervantes C), Nancy University Hospital (N = 12; Benetos A), Neris Les Bains Cabinet Medical (N = 5; Ollier J), Nice Hopital Cimiez (N = 3; David R), Niderviller Centre Readapt Spec Saint Luc (N = 2; Mechkour A), Nimes Centre Medical Delta (N = 6; Ghiba B), Nimes Hopital Caremeau (N = 3; Castelnovo G), Niort Cabinet Medical (N = 3; Le Bras F), Paris-Broca University Hospital (N = 16; Hanon O, Seux-Le Vieil ML), Paris-Lariboisière University Hospital (N = 7; Hugon J), Paris-La Salpétrière University Hospital Geriatry Department (N = 4; Verny M), Paris Cabinet Medical (N = 5; Delfiner B), Paris Cabinet Medical (N = 1; Defontaines B), Paris GH Paris Saint Joseph (N = 2; Volpe Gillot L), Perpignan Cabinet Medical (N = 9; Bailbe M), Pessac Hopital Xavier Arnozan (N = 3; Richard Harston S), Pompey Centre Hospitalier Intercommunal (N = 3; Durantay F), Quimper Centre Hospitalier de Cornouaille (N = 1; Diraison P), Quimperle Centre Hospitalier la Villeneuve (N = 9; Vaillant S), Rambouillet Cabinet Medical (N = 2; Gugenheim M), Rennes Cabinet Medical (N = 3; Hinault P), Reims University Hospital (N = 3; Novella JL), Rodez Centre Hospitalier Jacques Puel (N = 2; Hadjout K), Roquefort la Bedoule Domaine de la Source (N = 3; Bautrant T), Rouen University Hospital (N = 1; Hannequin D), Rouen Cabinet Medical (N = 6; Hemet Francois C), Rueil Malmaison Cabinet Medical (N = 3; Schmidt N), Saintes Centre Hospitalier de Saintonge (N = 1; Beaudout Agbo C), Sarreguemines Cabinet Medical (N = 6; Seiller N), St Aubin Sur Scie Clinique MegivaL (N = 2; Edouard T), St Claude Centre Hospitalier Louis Jaillon (N = 3; Sophoclis C), St Dizier Usld et Ehpad les Rives de Marne (N = 6; Badr A), St Georges de Didonne Atlantis (N = 4; Saudreau Furgier C), St Lizier Centre Hospitalier Ariege Couserans (N = 5; Del Mazo F), St Michel Centre Hospitalier (N = 3; Pin JC), St Nicolas De Port Centre Hospitalier (N = 1; Moreau Perrein F), St Palais CMC Sokorri (N = 3; Deyrolle AM), St Privat des Vieux Notre Dame des Pins (N = 9; Baudin V), St Quentin Cabinet Medical (N = 3; Crauser C), St Quentin Centre Hospitalier (N = 3; Gallopin V), Toulouse Hopital Purpan (N = 3; Pariente J), Toulouse University Hospital (N = 3; Lala F), Tourcoing Hopital Guy Chatiliez (N = 6; Gallouj K), Troyes Hopital des Hauts Clos (N = 3; Awad R), Valenciennes Residence du val D Escaut (N = 3; Renard P), Versailles Hopital Richaud (N = 3; Schott Geisert C), Vienne Centre Hospitalier Lucien Hussel (N = 1; Hascar T),Villejuif Hopital Paul Brousse (N = 5; BurlaudLaumond A, Guichardon M), Villeurbanne Cabinet Medical (N = 3; Chammas A), Vire Centre Hospitalier (N = 3; Wegener K)

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