Cognitive dysfunction associated with aluminum hydroxide-induced macrophagic myofasciitis: A reappraisal of neuropsychological profile

Accepted Manuscript Cognitive dysfunction associated with aluminum hydroxideinduced macrophagic myofasciitis: A reappraisal of neuropsychological profile

Mehdi Aoun Sebaiti, Paul Kauv, Anaïs Charles-Nelson, Axel Van Der Gucht, Paul Blanc-Durand, Emmanuel Itti, Romain K. Gherardi, Anne-Catherine Bachoud-Levi, François Jérôme Authier PII: DOI: Reference:

S0162-0134(17)30652-9 doi:10.1016/j.jinorgbio.2017.09.019 JIB 10340

To appear in:

Journal of Inorganic Biochemistry

Received date: Revised date: Accepted date:

30 June 2017 15 September 2017 19 September 2017

Please cite this article as: Mehdi Aoun Sebaiti, Paul Kauv, Anaïs Charles-Nelson, Axel Van Der Gucht, Paul Blanc-Durand, Emmanuel Itti, Romain K. Gherardi, Anne-Catherine Bachoud-Levi, François Jérôme Authier , Cognitive dysfunction associated with aluminum hydroxide-induced macrophagic myofasciitis: A reappraisal of neuropsychological profile. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Jib(2017), doi:10.1016/ j.jinorgbio.2017.09.019

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ACCEPTED MANUSCRIPT JINORGBIO_2017_345/Revised - Aoun-Sebaiti M et al. MMF-associated cognitive dysfunction – page

Ms # JINORBIO_2017_345 – Revised version

Cognitive dysfunction associated with aluminum hydroxide-induced

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macrophagic myofasciitis: A reappraisal of neuropsychological profile

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Mehdi AOUN SEBAITI1,2, Paul KAUV3, Anaïs CHARLES-NELSON4, Axel VAN DER

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GUCHT5, Paul BLANC-DURAND5, Emmanuel ITTI5, Romain K GHERARDI1,6, Anne-

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Catherine BACHOUD-LEVI2, François Jérôme AUTHIER1,6

Addresses

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1. INSERM/UPEC U955 Team 10 „Biology of Neuromuscular System‟, Faculty of Médecine, 94000 Créteil, France; 2. Department of Neurology, Henri Mondor University Hospital, 94000 Créteil; 3. Neuroradiology, Henri Mondor University Hospital, 94000 Créteil;

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4. Cordeliers Research Center, UPMC, Team „Information Sciences to support Personalized Medicine‟, 75006 Paris;

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5. Nuclear Medicine, Henri Mondor University Hospital, 94000 Créteil; 6. Expert Center for Neuromuscular Diseases, Department of Pathology, Henri Mondor University Hospital, 94000 Créteil;

Corresponding author:

FJ Authier, MD, PhD Expert Center for Neuromuscular Diseases, Department of Pathology, Henri Mondor University Hospital, 94000 Créteil, FRANCE Tel: +33 1 4981 2735 [email protected]

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Key words

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Macrophagic myofasciitis, Aluminum, Attention, Dysexecutive syndrom, Episodic memory, Dichotic listening

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Abstract Patients with macrophagic myofasciitis (MMF) present with diffuse arthromyalgias, chronic fatigue, and cognitive disorder. Representative features of MMF-associated cognitive dysfunction include attentional dysfunction, dysexecutive syndrome, visual memory deficit and left ear extinction. Our study aims to reevaluate the neuropsychological profile of MMF.

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105 unselected consecutive MMF patients were subjected to a neuropsychological battery of

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screen short term and long-term memory, executive functions, attentional abilities,

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instrumental functions and dichotic listening. From these results, patients were classified in four different groups: Subsymptomatic patients (n=41) with performance above pathological

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threshold (-1.65 SD) in all tests; Fronto-subcortical patients (n=31) who showed pathological results at executive functions and selective attention tests; Papezian patients (n=24) who

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showed pathological results in storage, recognition and consolidation functions for episodic verbal memory, in addition to fronto-subcortical dysfunction; and Extinction patients (n=9)

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who had a left ear extinction at dichotic listening test in association to fronto-subcortical and

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papezian dysfunction. In addition, inter-test analysis showed that patients with apparently normal cognitive functions (Subsymptomatic group) performed significantly worse to

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attention tests compared to others. In conclusion, our study shows that (i) most patients have specific cognitive deficits; (ii) all patients with cognitive deficit have impairment of executive

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functions and selective attention; (iii) patients without measurable cognitive deficits display significant weakness in attention; (iv) episodic memory impairment affects verbal, but not visual, memory; (v) none of the patients show an instrumental dysfunction.

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Graphical abstract

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Group 2 Fronto-sub-corticals: VSA deficit Dysexecutive syndrome

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Group 3 Papezians: VSA deficit Dysexecutive syndrome Episodic verbal memory deficit

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Group 4 Extinctions: VSA deficit Dysexecutive syndrome Episodic verbal memory deficit Left ear extinction

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Group 1 Subsymptomatics: Visual selective attentional (VSA) Weakness

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Neuropsychological evaluation allows stratification of macrophagic myofasciitis patients with

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cognitive complain in four groups of growing severity (1  4) with a continuum between

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them.

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Highlights 1. Most patients with macrophagic myofasciitis had specific cognitive deficits; 2. Cognitive impairment mainly affects executive functions and selective attention;

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4. None of studied patients showed an instrumental dysfunction.

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3. Patients without measurable cognitive deficits displayed weakness in attention;

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1. Introduction Macrophagic myofasciitis (MMF) is a rare condition characterized by highly specific myopathological alterations at deltoid muscle biopsy, recognized in 1998 [1] and shown to assess long-term persistence of vaccine-derived aluminum hydroxide nanoparticles within macrophages at the site of previous intramuscular injections [2]. Clinical manifestations

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observed in adult patients typically include chronic arthromyalgias, fatigue and cognitive

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difficulties [3,4,5]. The rate of fatigue was shown higher in MMF patient than others

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neuromuscular disorders, and mental fatigue (i.e, cognitive disturbance) represented its principal component [6]. Unlike other chronic pain syndromes where neuropsychological

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impairment usually results from the non-specific combination of pain, fatigue and depression [7,8], MMF-associated cognitive dysfunction (MACD) seems to reflect a more specific

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condition, not correlated with pain, fatigue, or depression, independent of symptoms duration,

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and stable with time [5,9].

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MMF associated cognitive dysfunction (MACD) includes episodic memory deficit, dysexecutive syndrome, attention impairment and in a lesser extend left ear extinction

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[5,9,10]. Neurocognitive disorders similar to that found in MMF may also be observed in various pathological conditions with acquired brain involvement, of inflammatory origin,

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such as multiple sclerosis or chronic infection by hepatitis C virus (HCV) or human immunodeficiency virus (HIV) [5]. Exposure to aluminum may also induce chronic alterations of visual memory, working memory and attention/concentration, as previously reported in hemodialyzed patients [11], metal inert gas welders [12], foundry workers [13] and people accidentally exposed to drinking aluminum sulfate-contaminated water [14], all these cases witnessing the well-known neurotoxicity of high levels of aluminum [9,15]. Routine neuropsychological evaluations of MMF patients followed in our center showed that the profile of cognitive impairment may notably vary from a patient to other, mainly in

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regards with dysexecutive features and memory impairment [9]. However, current knowledge on MACD is mainly based on studies included only a limited number of patients (n=25 in Couette et al. [5]; n=30 in Passeri et al. [9]). To improve the delineation of MACD, we retrospectively analyzed neuropsychological performances of an extended cohort of MMF patients (n=105) without any neurological or psychiatric disorder.

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2. Patients and methods

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2.1. Participants

This study was done in the Reference Center for Neuromuscular Diseases (NMD) of

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Henri Mondor University Hospital (Creteil, France), a specialized tertiary level structure dedicated to the diagnosis and care of adult NMDs. We examined medical files of 105

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unselected consecutive MMF patients. Inclusion criteria were: (i) the presence of MMF lesions at muscle biopsy detected more than 1 year after last immunization, (ii) the presence

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of myalgias, fatigue, and cognitive complaint at time of evaluation; (iii) duration of symptoms

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> 6 months; and (iv) at least one full neuropsychological assessment. Histological MMF lesions were defined by focal accumulations of cohesive large aluminum-loaded macrophages

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in epi, peri-, or endomysium, without formation of epithelioid or multinucleated giant cells [1,2,5]. Inclusion criteria for the study were: (i) symptomatic MMF (see criteria supra). Only

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patients without any other neurological (cerebrovascular, degenerative disease, epileptic or multiple sclerosis) or psychotic syndrome were included. Collection and analysis of data was retrospective and performed after de-identification (IRB approval Dec. 18, 2013, at CPP Ilede-France VI). 2.2.Clinical and neuroimaging evaluation Clinical and neuroimaging evaluation of patients was carried out within the context of routine care in our hospital. All patients were clinically evaluated by FJA. For each patient,

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clinical evaluation included medical history, symptoms notification and neurological examination. All included MMF patients underwent neuropsychological evaluation. Because of non-fortuitous association between MMF and MS [4,11] brain magnetic resonance imaging (MRI) was performed in 92/105 patients. All MRI data was acquired either on a 1.5 T Avanto or a 3.0 T Verio MRI system (Siemens, Germany) using a birdcage head coil 12-

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channels. Scans were collected with the following pulse sequences: T2-weighted images in

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axial plane (TR/TR: 3340/128 ms, flip angle: 150°, matrix: 256×256, voxel size: 0.9x0.9mm,

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slice thickness: 5mm, number of slices: 24), FLAIR in axial plane (TR/TE/TI: 8500/115/2438 ms, flip angle: 150°, matrix: 256x256, voxel size: 0.9x0.9mm, slice thickness: 5mm, number

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of slices: 24) and gadolinium-enhanced T1-weighted 3D images in sagittal plane (TE/TR: 2.47/1900 ms, flip angle: 9°, matrix: 256x246, voxel size: 0.5x0.5mm, slice thickness: 1mm,

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number of slices: 192). T2-weighted and FLAIR images to detect white matter lesion, and

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2.3.Neuropsychological evaluation

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enhanced lesions were review by one neuroradiologist blinded to clinical data.

Neuropsychological evaluation was conducted at the interventional platform of

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Créteil, France (INSERM/U955-Team 01) and targeted: short term memory evaluation by forward (immediate memory) and backward (working memory) digit span in the two

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modalities (verbal and visual modalities) [16,17]; episodic memory in verbal modality by Grober & Buschke test (G&B, free and cued recall) [18] and visual modality by Rey Osterrieth [19] (or Benton) complex figure (3 minutes recall after copy); executive functions by TMT A and B (GREFEX version) for flexibility, verbal fluency tasks in 2 minutes (“P” and “Animals”; GREFEX version) for generation of information, Stroop test (GREFEX version) for cognitive inhibition and ROCF copy for planning [19,20,21]; visual selective attention was evaluated by Zazzo‟s cancellation test (1, 2 and 3 signs) [22]; auditory extinction by dichotic listening protocol, in words and sentences conditions [23]. Finally,

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instrumental functions were assessed by oral denomination of 80 words (DO 80) (oral language) [24] and Mahieu‟s battery for evaluation of praxis (ideo-motors and motors praxis) [25]. A result at test was considered normal if the obtained value was superior of -1SD reference value for age and education level. A value located between -1SD and -1.65SD was considered like compromised function [26,27,28]. Pathological threshold was set at -1.65SD

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[26,27,28].

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Before neuropsychological evaluation, patient was checked for depression

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(Beck's Depression Inventory, BDI II) [29], fatigue (Visual Analogic Scale, VAS) and pain (VAS). For the depressive component, pathological threshold for depression scale is usually

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established at >11/63.

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2.4. Statistical analysis

Results were expressed as mean ± standard deviation. For each test, Z-scores were

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calculated in order to place obtained values in relation to pathological (-1.65SD) threshold.

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For each patient, Z was calculated from the formula Z=x-m/σ, x being patient‟s score. Zscores were not computed for dichotic listening test since no standard deviations are available

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for this test. We used threshold score established in terms of age of patients. In this way, it was possible to objective bad and good performers at each neuropsychological test and gather

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patients with similar level of performance. Descriptive statistics were used to objective the intra-group mean of scores obtained at each cognitive test. Fisher‟s exact test and Mann-Whitney‟s test was used to perform intergroup comparison on discriminating tests. Wilcoxon‟s test was used to evaluate intra-group differences between each cognitive test. Spearman‟s correlation test was applied to search a correlation between cognitive performances and depression, pain and fatigue levels. Finally, Friedman‟s Anova was used to test effect of time on retention abilities for patients with

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memory impairment. Statistical analyses were carried out using Statistica® 5.1 (97) (http://www.statsoft.fr/index.php).

3. Results

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3.1.Clinical evaluation

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One hundred and five patients were included. Sex-ratio was 1:2.75 (28 M/77 F).

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Ninety-two patients were right handed, nine were left handed and four were ambidextrous. Age of patients (mean±SD) at time of neuropsychological evaluation was 45±12.7 years. The

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delay elapsed between first symptoms and diagnosis (time of biopsy) was (mean±SD) 6±4.98 years (median: 4). The delay elapsed between first symptoms and neuropsychological

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evaluation was (mean±SD) 11.9±6.14 years (median: 11). The minimum persistence time of aluminum hydroxide within body, assessed by the delay elapsed between last injection of

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aluminum hydroxide-based vaccine and diagnostic muscle biopsy was (mean±SD)

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74.7±44.18 months (median: 60; range: 12-204). At cognitive evaluation, seventy-five patients (71%) reached depression threshold according to BDI II scale (score>11). Fifty-one

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patients (49%) reached 5/10 score at visual analogical scale (VAS) of pain, and seventy-four

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patients (70%) reached 5/10 scores at the scale of fatigue (EVA) (Table 1). 3.2. Neuroimaging evaluation Brain MRI was performed at Henri Mondor hospital in 92/105 patients included in our study. 69/92 showed non-specific brain supra-tentorial white matter T2-weighted, and cortical atrophy was observed in 5/92. MRI was normal in 23/92 subjects. 3.3. Neuropsychological evaluation and patient stratification (Figure 1-4)

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Among the twenty-seven evaluated neuropsychological variables, only two were correlated with pain and fatigue levels, TMT A (p<.005); p<.05) subtest and denomination condition of stroop test (p<.05; p<.05). Since these two sub-tests only revealed processing speed that is not strictly speaking a cognitive function, we can conclude that there is no

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hort term Memory

Zscores ≤-1,65

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Visual Selective Attention

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Executive Functions

-1,65 < Z scores ≤ -1 SD

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memoryLong term Verbal memory

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memoryLong term Visual memory

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Language

LES LEW DO 80 ROCF memory G&B Recognition G&B DTR G&B TR3 G&B TR2 G&B TR1 "Animals" Fluencies "P" Fluencies Stroop I-D TMT B-A C3 C2 C1 Backward DS Forward DS

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Dichotic Listening

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significant correlation between cognitive performance and depression, pain and fatigue levels.

Figure 1. Type I Subsymptomatic neuropsychological profile. Percentage of patients performing beyond the thresholds of weakness (-1.65SD
Patients were stratified in four distinct profiles according to the results of neuropsychological evaluation (for detailed results of neuropsychological evaluations see Supplemental data). A first group corresponds to 41 patients (39%; age [meanSD]: 4614.2) in whom no more than two sub-test reached the pathological threshold. However, all of these

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patients obtained score lower than normal (between -1.0 SD and -1.65 SD) at least at one executive or attentional test, most often Zazzo test for visual selective attention (23/41). Since this weakness relates to a key cognitive component of MACD, this neuropsychological profile was termed Subsymptomatic (Type I profile) (Figure 1). A second group corresponds to 31 patients (29%; age [meanSD]: 45.212.9) with

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pathological performances at visual selective attention and executive (inhibition and

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flexibility) tests. Since executive functions are anatomically underlied by fronto-subcortical

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loops [30,31,32,33,34], this neuropsychological profile was termed Fronto-subcortical (Type

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II profile; Figure 2).

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Dichotic Listening Language

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Long term Visual

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Executive Functions

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Long term Verbal

Visual Selective Attention

Short term MemoryS

Figure 2. Type II Fronto-subcortical neuropsychological profile. Percentage of patients performing beyond the thresholds of pathology (Z score≤-1.65SD) in the neuropsychological tests. Criteria defining the profile of cognitive dysfunction integrate the need to obtain two pathological scores at least two tests evaluating similar functions (executive functions, memory). For dichotic listening, patient must obtain score under pathological threshold established for age in both conditions (words and sentences) at the same ear (left or right).

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Detailed analysis showed that 16/31 patients had flexibility dysfunction (TMT-B), 14/31 cognitive inhibition deficit (Stroop test), and 18/31 visual selective attention deficit (Zazzo‟s cancellation test). A minority of patients obtained pathological scores at “P” (7/31) and “animals” (7/31) fluencies. The three item conditions of Zazzo‟s cancellation test was the sub-test the most significantly altered compared with the others (Figure 2).

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A third group corresponds to 24 patients (23%; age [meanSD]: 42.211.1) with scores under the pathological threshold at memory tests. 18/24 patients had impaired verbal

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long term memory, as assessed by pathological results at least two of four total recalls of

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G&B‟s memory test, revealing storage troubles of information in episodic memory. For all of

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them, results at delayed total recall of G&B‟s test were below -2SD witnessing the severity of memory impairment. 8/24 patients had impaired visual memory (ROCF), but only

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pathologically performed in both verbal and visual modalities.

LES LEW DO 80 ROCF memory G&B Recognition G&B DTR G&B TR3 G&B TR2 G&B TR1 "Animals" Fluencies "P" Fluencies Stroop I-D TMT B-A C3 C2 C1

Language Long term Visual memory

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Figure 3. Type III Papezian neuropsychological profile. Percentage of patients performing beyond the thresholds of pathology (Z score≤-1.65SD) in the neuropsychological tests. Criteria defining the profile of cognitive dysfunction integrate the need to obtain two pathological scores at least two tests evaluating similar functions (executive functions, memory). For dichotic listening, patient must obtain score under pathological threshold established for age in both conditions (words and sentences) at the same ear (left or right).

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In addition to this memory impairment, these patients showed an alteration of executive function and visual selective attention abilities similar to that observed in type II profile. In particular, 7/24 patients had pathological results at TMT test (flexibility), 8/24 at Stroop test (cognitive inhibition) and 16/24 at Zazzo‟s test (visual selective attention). 8/24

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were bad performers at “P” fluency and 6/24 at “animals” fluency (generation of information). Since storage dysfunctions in episodic memory involve Papez‟ circuit

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[35,36,37,38], this neuropsychological profile was termed Papezian (Type III profile, Figure

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3).

Long term Visual memory

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Zscores ≤-1,65

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Language

LEW DO 80 ROCF memory G&B Recognition G&B DTR G&B TR3 G&B TR2 G&B TR1 "Animals" Fluencies "P" Fluencies Stroop I-D TMT B-A C3 C2 C1 Backward DS Forward DS

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Figure 4. Type IV Extinction neuropsychological profile. Percentage of patients performing beyond the thresholds of pathology (Z score≤-1.65SD) in the neuropsychological tests. Criteria defining the profile of cognitive dysfunction integrate the need to obtain two pathological scores at least two tests evaluating similar functions (executive functions, memory). For dichotic listening, patient must obtain score under pathological threshold established for age in both conditions (words and sentences) at the same ear (left or right).

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Finally, in a small subset of patients (n=9,.9%; age [meanSD]: 50.65.1) displayed pathological performances at left ear for words and sentences conditions at dichotic listening test that suggests the existence of left ear extinction. All of them also had scores under pathological threshold at tests for episodic memory (5/9), executive functions (7/9) and attention (9/9). When present, memory impairment was severe as assessed by delayed total

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recall of G&B‟s test results below -2SD. This neuropsychological profile was termed

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Extinction (Type IV profile) (Figure 4).

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None of one hundred and five patients obtained pathological scores at instrumental function tests (DO 80, praxis).

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3.4. Intergroup analysis (Table 1)

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There was no significant difference for age between each group (Table 1). However patients aged <50 yrs were more numerous than those >50yrs in „Papezian’ group (18/24 in

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group III vs 38/81 in groups I+II+IV, p=0.02). On the contrary all „Extinction’ patients but

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one, were >50 yrs, and the proportions of patients over or below 50yrs were similar in „Subsymptomatic and „Fronto-subcortical’ groups (Type I: 21/41 <50yrs; Type II: 16/31

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<50yrs). In addition, Papezian patients displayed higher depression levels (BDI scale) compared to others (I vs III: p=0.05; II vs III: p=0.025; III vs IV: p=0.028). Importantly,

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intragroup analysis did not show any correlation between BDI scores and cognitive performances whatever the group considered. Regarding gender, sociocultural level, fatigue and pain levels, duration time of disease at time of diagnosis and neuropsychological evaluation, and persistence time of aluminum hydroxide within body, no difference was observed between the four groups of patients (Table 1). Logically, Subsymptomatic patients performed better than patients from other groups for all tests included in neuropsychological assessment. No significant difference was observed for attentional and executive tests between Fronto-subcortical, Papezians, and Extinction patients. Finally, we did not found any

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significant difference in episodic memory performances between Papezian and Extinction patients.

Depression: BDI II2 score (mean ± SD; mediane) 3

Delta onset-diagnosis (mean ± SD)

Profile IV 9 6/3 50.6;44-59 4-6

6.4±2.7;7,15 6.1±2.9;7,2 6.5±2.5;7.3 4.5±2.42;4.8 3.9±2.5;4.8 4.8±2.3;5

7.5±2.2;7.8 5.2±2.5;4.7

6±3.6;5 4.3±1.9;4.8

17±9.4;15 6±4.98

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11.9±6.14

16±9.6;15

15±8.5;15

21.3±10.3;23

14±5.1;14

5.5±3.91

7.5±6.45

5.5±4.72

5.2±4.49

11.4±5.96

12.5±6.79

11.6±5.93

13.3±6.44

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Delta onset-NP (mean ± SD) 5

74.67;12-204 72;12-144 69.17;12-204 74.12;36-192 102.86;36-192

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Persistence (mean; range)

Profile II 31 28/3 45.2;16-62 3-7

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Fatigue : VAS1 score (mean ± SD; mediane) Pain : VAS score (mean ± SD; mediane)

Profile I 41 25/16 46;16-71 3-7

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Total 105 77/28 45;16-71 3-7

n Gender Ratio F/M Age (mean; range) SCL (min-max)

Profile III 24 18/6 42.2;22-64 3-7

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Table 1. Demographical and clinical features in 105 patients with macrophagic myofasciitis

Discussion

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Notes: (1) VAS: visual analogic scale; (2) BDI: Beck‟s Depression Inventory; (3) Diagnosis date is that of muscle biopsy showing MMF lesions; (4) Neuropsychological evaluation; (5) Persistence time corresponds to the delay elapsed between last injection of aluminum hydroxide-adjuvanted vaccine in biopsied deltoid muscle and the date of biopsy.

This work confirms and extends our previous studies depicting macrophagic

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myofasciitis-associated cognitive dysfunction (MACD) [5,9], with the opportunity to analyze a very large cohort that allowed us to accurately refine the cognitive phenotype of patients. In line with previous data, fronto-subcortical dysfunctioning was the prominent feature of MACD, as attested by the impairment of attention and executive functions including working memory, planning, flexibility, and inhibition. Despite limitations mainly due to the retrospective nature of study and the lack of agematched controls, our results provided interesting insights about MACD. First, in line with our previous findings [5,9], present study confirmed that cognitive dysfunction in MMF

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patients cannot be simply explained by non-specific factors such as pain, fatigue and depression. This point is of peculiar importance since cognitive impairment in MMF patients is often underestimated and usually ascribed to depression. Similarly, drug intake does not seem to significantly impact cognitive functioning in MMF patients [9] that may be explained, at least in part, by the benefit of pain or depression alleviation. However, the real

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novelty brought by this study lies in the possibility to stratify patients according to four different neuropsychological profiles corresponding to groups of growing severity.

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Delineating different neuropsychological profiles is important routine care for different

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reasons. First, cognitive rehabilitation approaches differ according to neuropsychological

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profile. Second, the presence of cognitive deficit may lead to perform additional investigations such as neurodegeneration biomarkers quantification in cerebrospinal fluid.

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Third, the quantification of handicap depends on the type of cognitive impairment. The first group corresponds to patients with subjective cognitive complaint, but without definite

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cognitive deficit, according to the -1.65SD threshold. Such individuals represent a not

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negligible part of our patients (39%), but have not been clearly identified until now. Interestingly, these patients displayed poorer performances at attention tasks compared to

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other tests. Attention is most particularly impaired in patients with full-blown cognitive deficit, and therefore these patients can be considered as having a mild form of MACD

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leading us to term their profile „Subsymptomatic‟ instead of asymptomatic or normal. In the other hand, considering patients with definite cognitive deficit (64/105, 61%), all had significant impairment in attention and executive functions that can associate or not with additional deficits, delineating the three other profiles: „Fronto-subcortical‟ or type II, „Papezian‟ or type III, „Extinction‟ or type IV. In „Papezian‟ group, memory impairment was severe (<-2SD at G&B delayed total recall) in 18/24, and therefore may notably contribute to cognitive disability. Most „Extinction’ patients had also memory impairment and therefore left ear extinction at dichotic listening can be regarded as an additional degree in severity of cognitive dysfunction. Finally, from this cohort, MACD appears more homogeneous than

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suggested by the stratification in different profiles, with attentional deficit as the main thread,

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Group 2 Fronto-sub-corticals: VSA deficit Dysexecutive syndrome

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Group 3 Papezians: VSA deficit Dysexecutive syndrome Episodic verbal memory deficit

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Group 4 Extinctions: VSA deficit Dysexecutive syndrome Episodic verbal memory deficit Left ear extinction

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Group 1 Subsymptomatics: Visual selective attentional (VSA) Weakness

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and a continuum reflecting the spreading of neuropsychological involvement (Figure 5).

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Figure 5. Continuum between the four neuropsychological profiles described in MMF patients with cognitive complaint „Papezian‟ group differs from others by a higher proportion of patients aged below 50, pointing out the potential severity of MACD. The observation of younger patients with more

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severe cognitive impairment is a worrying finding that remains unexplained so far. These

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patients were also more often depressed than those from other groups but their cognitive deficits did not correlate with BDI scores. Memory deficits in our patients typically implicate information storage and consolidation, functions commonly considered as unaffected by depression when encoding phase is controlled by testing procedure. Memory dysfunction usually relates to hippocampal areas involvement [35,36,37,38]. In the other hand, recent studies support a role for hippocampus in the regulation of emotions [39,40]. The implication of hippocampus in mood is supported by occasional clinical reports showing that limbic encephalitic may present at onset with isolated mood disorders [41], and by experimental data showing that inflammatory changes of hippocampus in ovariectomized female rats can

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produce depression behavior [42]. In our „Papezian‟ patients, routine MRI was unremarkable and none of these patients were considered as having an inflammatory CNS disease. The stability with time of cognitive deficits in MMF patients [9] and the lack of instrumental functions dysfunctionning [43,44,45] do not speak in favor of a neurodegenerative process. Anyway, further functional and morphological imaging investigations seem needed to explore

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and understand this feature. Likewise, the quantification of neurodegeneration biomarkers  Tau protein, phosphorylated Tau protein, and amyloid Aβ1-42 and Aβ1-40 peptides  and of

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aluminum in cerebrospinal fluid should be considered in further studies dealing with MACD. As previously reported [5,9], routine brain MRI appears only poorly contributive for

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investigating MACD, but remains required in the diagnostic workup to detect multiple sclerosis-type inflammatory changes [46]. In present cohort, brain MRI was available in

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92/105 (88%) and was normal or unspecific in 87 of the 92 patients (95%) of the patients. The remaining 5 patients had mild diffuse cortical atrophy, a feature not explained to date. As

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previously stated [9], it seems logical to investigate whether MACD patients with atrophy

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may constitute a specific subgroup with regard to their evolution. In a recent study using 18FFDG positon emission tomography (PET) [47], we reported a peculiar spatial pattern of

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cerebral glucose hypometabolism involving involving the occipital lobes, temporal lobes, limbic system, cerebellum, and frontoparietal cortices. Among our 105 patients, 86 underwent

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FDG-PET that showed typical posterior hypometabolism profile in 58 (67%). It has been well established that cerebellum plays a role in cognitive processes, particularly in executive functions [48]. This feature relates to the numerous connections between the cerebellum and cortical areas through the cortico-ponto-cerebellar pathways [47,49]. FDG-PET hypometabolism notably affects limbic system, including the amygdalohippocampal/entorhinal complexes and cingulate gyrus, which plays a key role in long-term memory storage and consolidation, and is involved in the Papez circuit [35,36,37,38].

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There has long been a missing conceptual link between long-term persistence of adjuvant particles within macrophages at the site of previous immunization and the occurrence of adverse neurological events in patients with MMF [50]. The neurotoxic effects of aluminum include cognition impairment, blood-brain barrier damages, neurotransmission and synaptic activity alterations, microglia activation, the depression of cerebral glucose

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metabolism and mitochondrial functions, interferences with gene transcription, and the promotion of beta-amyloid and neurofilament aggregation [51]. Concerns about bio-persistent

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adjuvants largely depend on ability of Al3+ to reach remote organs and the brain and exert its

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toxicity in critical sites. Several studies from the literature have suggested such an occurrence

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[52,53,54,55,56], but whether adjuvant-derived aluminum reaches the brain in its native particulate or in a soluble form remained undetermined [50]. Experimental data showed that,

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after intramuscular injection, nanosized particles are quickly captured by monocyte-lineage cells which rapidly formed a persistent local granuloma but also served as a vehicle for

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transportation of particle from the injected muscle to the draining lymph node, the spleen,

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blood circulation and remote tissues or organs including the brain [50, 57,58,59]. Once entered within brain, aluminum deposits in cortex, corpus callosum, and hippocampus [60].

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The systemic biodistribution of particles crucially depends on MCP-1/CCL2 the major monocyte chemoattractant [59]. The imbalance between the huge number of vaccinated

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individuals and the relatively low number of MMF cases suggests that individual susceptibility factors, related to ageing or other environmental factors or genetic traits, may play a crucial role in intolerance to aluminum adjuvants [50]. For example, selective increase of circulating MCP-1/CCL2 was identified as a circulating biomarker in patients with MMF [61] and could relates to constitutive genetically-determined overproduction [59]. For decades, vaccination has demonstrated its effectiveness in the control of devastating infectious diseases for the greater benefit of mankind. Vaccine safety has been regarded as excellent at the level of the population [62], but adverse effects have also been

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reported [63]. We believe that the understanding of mechanisms at work in patients with MMF should help to identify genetically-determined susceptibility factors that lead predisposed individuals to develop adverse effects following exposure to aluminum-based adjuvants. It is likely that the same mechanisms underlie the occurrence of unexpected troubles in case of sustained contact with other inorganic particles such as in context of

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occupational exposure, air pollution, or esthetic implants.

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Table of abbreviations

Beck Depression Scale

DO

Oral Denomination

EVA

Visual Analogic Scale

F-FDG

Fluorodesoxyglucose

FSC

Fronto-Subcortical

G&B

Grober and Buschke

GREFEX

Reflexion Group for the study of Executive Functions

HCV

Hepatitis C Virus

HIV

Human Immunodeficiency Virus

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BDI

Left ear sentences

LEW

Left ear words

MCI

Mild Cognitive Impairment

MMF

Macrophagic Myofasciitis

MR

Magnetic Resonance

MRI

Magnetic Resonance Imaging

MS

Multiple Sclerosis

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LES

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MACD Macrophagic myofasciitis Associated Cognitive Dysfunction

Nonsteroidal Anti-Inflammatory Drugs

PET-CT

Positron Emission Tomography-Computed Tomography

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NSAID

RES

Right ear sentences

REW

Right ear words

ROCF

Rey-Osteyrrieth Complex Figure

SD

Standard Deviation

TMT

Trail Making Test

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Acknowledgments

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This work was supported by a grant from French research program "Partenariats Institutions-Citoyens pour la Recherche et l‟Innovation" (PICRI) 2015. M. Aoun Sebaiti was recipient of a grant from the French patients' association "Entraide des Malades de la Myofasciite à Macrophages" (E3M). Research team „Biology of NeuroMuscular System‟ (INSERM/UPEC U955 Team 10) and GNMH reference center (Centre de référence Maladies Neuromusculaires : Garches - Necker - Mondor - Hendaye) is supported by grants from the "Association Française contre les Myopathies" (AFM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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References

[1] Gherardi, R. K., Coquet, M., Cherin, P., Authier, F. J., Laforêt, P., Belec, L., ... & Fardeau, M. (1998). Macrophagic myofasciitis: an emerging entity. The Lancet, 352(9125), 347-352. [2] Gherardi, R. K., Coquet, M., Cherin, P., Belec, L., Moretto, P., Dreyfus, P. A., ... & Authier, F. J. (2001). Macrophagic myofasciitis lesions assess long-term persistence of vaccine-derived aluminium hydroxide in muscle. Brain, 124(9), 1821-1831.

RI

PT

[3] Authier, F. J., Sauvat, S., Champey, J., Drogou, I., Coquet, M., & Gherardi, R. K. (2003). Chronic fatigue syndrome in patients with macrophagic myofasciitis. Arthritis & Rheumatology, 48(2), 569-570.

SC

[4] Gherardi, R. K., & Authier, F. J. (2003). Aluminum inclusion macrophagic myofasciitis: a recently identified condition. Immunology and allergy clinics of North America, 23(4), 699712. (2003) 699–712.

MA

NU

[5] Couette, M., Boisse, M. F., Maison, P., Brugieres, P., Cesaro, P., Chevalier, X., ... & Authier, F. J. (2009). Long-term persistence of vaccine-derived aluminum hydroxide is associated with chronic cognitive dysfunction. Journal of inorganic biochemistry, 103(11), 1571-1578.

D

[6] AFSSAPS (Agence Française de Sécurité Sanitaire des Produits de Santé), Etude épidémiologique exploratoire de la myofasciite à macrophages. Rapport d'étude, Octobre 2003http://www.afssaps.fr/var/afssaps_site/storage/original/application/ 030593fa4e393af7cec8ff7092832215.pdf, (accessed March 24th, 2009).

PT E

[7] Iezzi, T., Archibald, Y., Barnett, P., Klinck, A., & Duckworth, M. (1999). Neurocognitive performance and emotional status in chronic pain patients. Journal of behavioral medicine, 22(3), 205-216.

CE

[8] Suhr, J. A. (2003). Neuropsychological impairment in fibromyalgia: relation to depression, fatigue, and pain. Journal of psychosomatic research, 55(4), 321-329.

AC

[9] Passeri, E., Villa, C., Couette, M., Itti, E., Brugieres, P., Cesaro, P., ... & Authier, F. J. (2011). Long-term follow-up of cognitive dysfunction in patients with aluminum hydroxideinduced macrophagic myofasciitis (MMF). Journal of inorganic biochemistry, 105(11), 14571463. [10] Rigolet, M., Aouizerate, J., Couette, M., Ragunathan-Thangarajah, N., Aoun-Sebaiti, M., Gherardi, R. K., ... & Authier, F. J. (2014). Clinical features in patients with long-lasting macrophagic myofasciitis. Frontiers in neurology, 5. [11] Bolla, K. I., Briefel, G., Spector, D., Schwartz, B. S., Wieler, L., Herron, J., & Gimenez, L. (1992). Neurocognitive effects of aluminum. Archives of Neurology, 49(10), 1021-1026. [12] Akila, R., Stollery, B. T., & Riihimäki, V. (1999). Decrements in cognitive performance in metal inert gas welders exposed to aluminium. Occupational and environmental medicine, 56(9), 632-639.

ACCEPTED MANUSCRIPT JINORGBIO_2017_345/Revised - Aoun-Sebaiti M et al. MMF-associated cognitive dysfunction – page 25

[13] Polizzi, S., Pira, E., Ferrara, M., Bugiani, M., Papaleo, A., Albera, R., & Palmi, S. (2002). Neurotoxic effects of aluminium among foundry workers and Alzheimer‟s disease. Neurotoxicology, 23(6), 761-774. [14] Laskus, T., Radkowski, M., Adair, D. M., Wilkinson, J., Scheck, A. C., & Rakela, J. (2005). Emerging evidence of hepatitis C virus neuroinvasion. Aids, 19, S140-S144. [15] Bondy, S. C. (2010). The neurotoxicity of environmental aluminum is still an issue. Neurotoxicology, 31(5), 575-581.

PT

[16] Wechsler, D. (2000). Manuel: Echelle d‟intelligence pour adultes, 3e édition (WAIS-III). Paris: Les Editions du centre de Psychologie Appliquée.

RI

[17] Corsi, P. M., & Michael, P. (1972). Human memory and the medial temporal region of the brain (Vol. 34, p. 819B). Montreal: McGill University.

NU

SC

[18] Van der Linden, M., Coyette, F., Poitrenaud, J., Kalafat, M., Calicis, F., Wyns, C., & Adam, S. (2004). L'épreuve de rappel libre/rappel indicé à 16 items (RL/RI-16) (pp. 25-47). Solal.

MA

[19] Rey, A. (1959). Manuel: Test de copie et de reproduction de mémoire de figures géometriques complexes, eds. du Centre de Psychologie Appliquée. [20] Godefroy, O. (2008). Fonctions exécutives et pathologies neurologiques et psychiatriques: évaluation en pratique clinique. Groupe de Boeck.

PT E

D

[21] Meulemans, T. (2008). L‟évaluation des fonctions exécutives. In O. Godefroy, & GREFEX (Eds.), Fonctions exécutives et pathologies neurologiques et psychiatriques (pp.217-230). Solal. [22] Zazzo, R., Galifret-Granjon, N., Hurtig, M. C., & Santucci, H. (1965). Manuel pour l'examen psychologique de l'enfant. Delachaux et Niestlé.

CE

[23] Kimura, D. (1961). Some effects of temporal-lobe damage on auditory perception. Canadian Journal of Psychology/Revue canadienne de psychologie, 15(3), 156.

AC

[24] Deloche, G., & Hannequin, D. (1997). et Collaborateurs. DO 80, Epreuve de dénomination orale d'images [DO80: Eighty pictures: confrontation oral naming battery]. [25] Mahieux-Laurent, F., Fabre, C., Galbrun, E., Dubrulle, A., Moroni, C., & Groupe de réflexion sur les praxies du CMRR Ile-de-France Sud. (2009). Validation d‟une batterie brève d‟évaluation des praxies gestuelles pour consultation Mémoire. Evaluation chez 419 témoins, 127 patients atteints de troubles cognitifs légers et 320 patients atteints d‟une démence. Revue Neurologique, 165(6), 560-567. [26] Bouma, A., Mulder, J., Lindeboom, J., & Schmand, B. A. (2012). Handboek neuropsychologische diagnostiek.-2e herz. dr. [27] Lezak MD, Howieson DB, Bigler ED, Tranel D. Neuropsychological assessment. Oxford: Oxford University Press; 2012.

ACCEPTED MANUSCRIPT JINORGBIO_2017_345/Revised - Aoun-Sebaiti M et al. MMF-associated cognitive dysfunction – page 26

[28] Van den Berg E, Kessels RPC, De Haan EH, Kappelle LJ, Biessels GJ. Mild impairments in cognition in patients with type 2 diabetes mellitus: the use of the concepts MCI and CIND. J Neurol Neurosurg Psychiatry. 2005;76:1466–1467. doi: 10.1136/jnnp.2005.062737. [29] Beck, A. T., Steer, R. A., & Brown, G. K. (1996). Beck depression inventory-II. San Antonio, 78(2), 490-8.

PT

[30] Godefroy, O., Azouvi, P., Robert, P., Roussel, M., LeGall, D., & Meulemans, T. (2010). Dysexecutive syndrome: diagnostic criteria and validation study. Annals of neurology, 68(6), 855-864.

RI

[31] Godefroy, O., Jeannerod, M., Allain, P., & Le Gall, D. (2008). Lobe frontal, fonctions exécutives et contrôle cognitif. Revue neurologique, 164, S119-S127.

SC

[32] Godefroy, O., Roussel-Pieronne, M., Duclercq, I., Duval, L., & PETITCHENAL, V. (2001). Attention et pathologie frontale. In Forum de la Société de Neuropsychologie de Langue Française. La neuropsychologie de l’attention (pp. 175-192).

NU

[33] Graybiel, A. M. (1997). The basal ganglia and cognitive pattern generators. Schizophrenia bulletin, 23(3), 459-469.

MA

[34] Divac, I. (1972). Neostriatum and functions of prefrontal cortex. Acta neurobiol. exp, 32(2), 461-477.

D

[35] Milner, B., Corkin, S., & Teuber, H. L. (1968). Further analysis of the hippocampal amnesic syndrome: 14-year follow-up study of HM. Neuropsychologia, 6(3), 215-234.

PT E

[36] Papez, J. W. (1937). A proposed mechanism of emotion. Archives of Neurology & Psychiatry, 38(4), 725-743.

CE

[37] Zola-Morgan, S., Squire, L. R., & Amaral, D. G. (1986). Human amnesia and the medial temporal region: enduring memory impairment following a bilateral lesion limited to field CA1 of the hippocampus. Journal of Neuroscience, 6(10), 2950-2967.

AC

[38] Eichenbaum, H. (2000). A cortical–hippocampal system for declarative memory. Nature Reviews Neuroscience, 1(1), 41-50. [39] Fanselow, M. S., & Dong, H. W. (2010). Are the dorsal and ventral hippocampus functionally distinct structures?. Neuron, 65(1), 7-19. [40] Catani, M., Dell‟Acqua, F., & De Schotten, M. T. (2013). A revised limbic system model for memory, emotion and behaviour. Neuroscience & Biobehavioral Reviews, 37(8), 17241737. [41] Saladini, O., Gelin, V., Bidault, E., Remy, C., Antoine, J. C., & Luauté, J. P. (2011, June). Syndrome dépressif et encéphalite limbique: à propos d‟un cas. In Annales Médicopsychologiques, revue psychiatrique (Vol. 169, No. 5, pp. 312-314). Elsevier Masson.

ACCEPTED MANUSCRIPT JINORGBIO_2017_345/Revised - Aoun-Sebaiti M et al. MMF-associated cognitive dysfunction – page 27

[42] Wang, Y., Xu, Y., Sheng, H., Ni, X., & Lu, J. (2016). Exercise amelioration of depression-like behavior in OVX mice is associated with suppression of NLRP3 inflammasome activation in hippocampus. Behavioural brain research, 307, 18-24. [43] Serra, L., Fadda, L., Perri, R., Spanò, B., Marra, C., Castelli, D., ... & Bozzali, M. (2014). Constructional apraxia as a distinctive cognitive and structural brain feature of pre-senile Alzheimer's disease. Journal of Alzheimer's Disease, 38(2), 391-402.

PT

[44] Soulsby, W. D., El-Ruwie, N., Gatla, S., Zimmer, K. A., Najmi, S., Chen, A., ... & Grossberg, G. T. (2016). Ideomotor limb apraxia as a staging tool in individuals with Alzheimer's disease (ILIAD). Annals of Clinical Psychiatry, 28(4), 255-262.

RI

[45] Eustache, F., Bejanin, A., Lambert, J., Laisney, M., & Desgranges, B. (2015). Langage et démences: quelques illustrations dans la maladie d‟Alzheimer et la démence sémantique. Revue de neuropsychologie, 7(1), 56-62.

NU

SC

[46] Authier FJ, Cherin P, Creange A, Bonnotte B, Ferrer X, Abdelmoumni A, et al. Central nervous system disease in patients with macrophagic myofasciitis 6. Brain. 2001;124(Pt 5):974-83.

MA

[47] Van Der Gucht, A., Sebaiti, M. A., Itti, E., Aouizerate, J., Evangelista, E., Chalaye, J., ... & Authier, F. J. (2015). Neuropsychological correlates of brain perfusion SPECT in patients with macrophagic myofasciitis. PloS one, 10(6), e0128353.

D

[48] Schmahmann, J. D. (2004). Disorders of the cerebellum: ataxia, dysmetria of thought, and the cerebellar cognitive affective syndrome. The Journal of neuropsychiatry and clinical neurosciences, 16(3), 367-378.

PT E

[49] Schmahmann, J. D., Doyon, J., McDonald, D., Holmes, C., Lavoie, K., Hurwitz, A. S., ... & Petrides, M. (1999). Three-dimensional MRI atlas of the human cerebellum in proportional stereotaxic space. Neuroimage, 10(3), 233-260.

AC

CE

[50] Gherardi, R. K., Aouizerate, J., Cadusseau, J., Yara, S., & Authier, F. J. (2016). Aluminum adjuvants of vaccines injected into the muscle: Normal fate, pathology and associated disease. Morphologie, 100(329), 85-94. [51] Tomljenovic, L. (2011). Aluminum and Alzheimer's disease: after a century of controversy, is there a plausible link?. Journal of Alzheimer's Disease, 23(4), 567-598. [52] Flarend, R. E., Hem, S. L., White, J. L., Elmore, D., Suckow, M. A., Rudy, A. C., & Dandashli, E. A. (1997). In vivo absorption of aluminium-containing vaccine adjuvants using 26Al. Vaccine, 15(12-13), 1314-1318. [53] Redhead, K., Quinlan, G. J., Das, R. G., & Gutteridge, J. M. C. (1992). Aluminumadjuvanted vaccines transiently increase aluminium levels in murine brain tissue. Basic & Clinical Pharmacology & Toxicology, 70(4), 278-280. [54] Şahin, G., Varol, I., Temizer, A., Benli, K., Demirdamar, R., & Duru, S. (1994). Determination of aluminum levels in the kidney, liver, and brain of mice treated with aluminum hydroxide. Biological trace element research, 41(1-2), 129-135.

ACCEPTED MANUSCRIPT JINORGBIO_2017_345/Revised - Aoun-Sebaiti M et al. MMF-associated cognitive dysfunction – page 28

[55] Wang, X. Y., Yao, X., Wan, Y. M., Wang, B., Xu, J. Q., & Wen, Y. M. (2013). Responses to multiple injections with alum alone compared to injections with alum adsorbed to proteins in mice. Immunology letters, 149(1), 88-92. [56] Wen, G. Y., & Wisniewski, H. M. (1985). Histochemical localization of aluminum in the rabbit CNS. Acta neuropathologica, 68(3), 175-184.

PT

[57] Crépeaux, G., Eidi, H., David, M. O., Tzavara, E., Giros, B., Exley, C., ... & Cadusseau, J. (2015). Highly delayed systemic translocation of aluminum-based adjuvant in CD1 mice following intramuscular injections. Journal of inorganic biochemistry, 152, 199-205.

RI

[58] Eidi, H., David, M. O., Crépeaux, G., Henry, L., Joshi, V., Berger, M. H., ... & Curmi, P. A. (2015). Fluorescent nanodiamonds as a relevant tag for the assessment of alum adjuvant particle biodisposition. BMC medicine, 13(1), 144.

SC

[59] Khan Z, Combadiere C, Authier FJ, Itier V, Lux F, Exley C, et al. Slow CCL2-dependent translocation of biopersistent particles from muscle to brain. BMCMed. 2013;11:99.

MA

NU

[60] Yang, X., Yuan, Y., Lu, X., Yang, J., Wang, L., Song, J., ... & Niu, Q. (2015). The relationship between cognitive impairment and global DNA methylation decrease among aluminum potroom workers. Journal of occupational and environmental medicine, 57(7), 713-717.

D

[61] Cadusseau, J., Ragunathan-Thangarajah, N., Surenaud, M., Hue, S., Authier, F. J., & K Gherardi, R. (2014). Selective elevation of circulating CCL2/MCP1 levels in patients with longstanding post-vaccinal macrophagic myofasciitis and ASIA. Current medicinal chemistry, 21(4), 511-517.

PT E

[62] Moxon, E. R., & Siegrist, C. A. (2011). The next decade of vaccines: societal and scientific challenges. The Lancet, 378(9788), 348-359.

AC

.

CE

[63] Agmon-Levin, N., Paz, Z., Israeli, E., & Shoenfeld, Y. (2009). Vaccines and autoimmunity. Nature Reviews Rheumatology, 5(11), 648-652.