Pierre Lannelongue

Steven Le Vot

Olivier Fontaine

Thierry Brousse

Frédéric Favier

Fréderic Favier
email: frederic.favier@umontpellier.fr

Electrochemical study

Keywords: Aqueous electrochemical capacitors, Supercapacitors, Asymmetric devices, Volumetric energy density, BSCF, FeWO 4, Perovskite

Introduction

Electrochemical capacitors, also called supercapacitors, present intermediate performance between batteries and conventional capacitors [START_REF] Conway | Electrochemical Supercapacitors: Scientific Fundamentals and Technological Applications[END_REF]. Currently, commercialized electrochemical capacitors are electrochemical double layer capacitors (BSCF) a EDLCs) using activated carbon as electrodes. Their specific energy and power densities are about 10 Wh.kg -δ1 [1 ] and 10 kW.kg -δ1

[2 ], respectively. However, their volumetric energy density is low, typically between 5 and 7 Wh.L -δ1 . As such, EDLCs are not the ideal devices for power applications where the volume dedicated to energy storage is limited, such as in modern electrical terrestrial vehicles.

Another type of electrochemical capacitors has been developed over the past two decades, using materials showing a pseudocapacitive behavior. The pseudocapacitive charge storage process induces a similar electrochemical signature to that of capacitive process, but its origin is faradic and involves fast and reversible redox reactions twice greater than that of a symmetrical carbon/carbon device (BSCF) a bulk density: 2.09-δ2.23 g.cm -δ3 ) while keeping the same gravimetric specific energy [START_REF] Goubard-Bretesché | Improving the Volumetric Energy Density of Supercapacitors[END_REF].

Thus, high density pseudocapacitive oxides have to be considered to improve the volumetric energy density of electrochemical capacitors. This is in the last few years only that multicationic oxides have been studied as electrode materials for electrochemical capacitors These materials present high densities but also specific capacitances close to that of standard activated carbon. In previous papers, some of us have reported the attractive properties of two oxides to be used as electrode materials for electrochemical capacitors: FeWO 4 [28 ] and Ba 0.5 Sr 0.5 Co 0.8 Fe 0.2 O 3-δδ , so called BSCF [START_REF] Lannelongue | Investigation of Ba 0.5 Sr 0.5 Co x Fe 1-x O 3-δ as a pseudocapacitive electrode material with high volumetric capacitance[END_REF]. An asymmetric aqueous electrochemical capacitors with a FeWO 4 negative electrode material has already been tested using MnO 2 as the positive electrode [START_REF] Goubard-Bretesché | Electrochemical study of aqueous asymmetric FeWO 4 /MnO 2 supercapacitor[END_REF]. This device presents a specific capacitance of 9 F.g -δ1 (BSCF) a total weight of both electrodes) at 20 mV.s -δ1 in 5M LiNO 3 with a high cycling ability over 40,000 cycles.

The crystallographic density of FeWO 4 and BSCF materials is 7.5 and 5.8 g.cm -δ3 , respectively, i.e. 6 to 7 times greater than that of standard activated carbon. As such, both materials present high volumetric capacitance in aqueous medium (BSCF) a 5M LiNO 3 ). Furthermore, their respective operational potential windows are complementary (BSCF) a -δ0.6 -0 V vs Ag/AgCl for FeWO 4 and 0 -0.8 V vs Ag/AgCl for BSCF). Thus, it seems interesting to evaluate the volumetric performance of such electrochemical capacitor devices built from these two electrode materials.

Electrochemical capacitor devices with BSCF positive electrodes have never been reported in the literature. As such, we report hereafter the study of two asymmetric devices: the first one associates an activated carbon electrode with a BSCF electrode (BSCF) a C/BSCF) and the second one associates FeWO 4 and BSCF electrodes (BSCF) a FeWO 4 /BSCF). Both devices were operated in aqueous 5M LiNO 3 electrolyte. Several devices have been built and tested to determine the conditions, in terms of electrode weight ratios and current densities, allowing a good compromise between performances and electrochemical stability window of each electrode. Specific and volumetric performance and cycling ability of these devices have been evaluated by galvanostatic cycling. Self-δdischarge measurements have been performed by a chronoamperometry/chronopotentiometry routine. Performance of these devices are commented to argue on the interest of using high density electrode materials to improve the volumetric energy density of electrochemical capacitors.

Experimental section

Materials

Ba 0.5 Sr 0.5 Co 0.8 Fe 0.2 O 3-δδ - BSCF BSCF All precursors were purchased from Sigma Aldrich. Precursors mass used are listed in Tab.S1. BSCF was prepared by a modified glycine-δnitrate process. Ba(BSCF) a NO 3 ) 2 (BSCF) a ACS Reagent, ≥99%), Sr(BSCF) a NO 3 ) 2 (BSCF) a ACS Reagent, ≥99%), Co(BSCF) a NO 3 ) 2 ,6H 2 O (BSCF) a ACS Reagent, ≥98%) and Fe(BSCF) a NO 3 ) 3 ,9H 2 O (BSCF) a ACS Reagent, ≥98%) were dissolved in stoichiometric quantities in distilled water at 100°C and under vigorous stirring. A red solution is obtained. After dissolution, glycine (BSCF) a ACS Reagent, ≥98.5%), acting as complexing agent and fuel, was added to the solution. Ten minutes after glycine dissolution, ethylenediaminetetraacetique acid EDTA, acting as complexing agent (BSCF) a anhydrous, ≥99%) was added. The stoichiometry quantities of glycine and EDTA were determined following reactions pathways (BSCF) a 1) and (BSCF) a 2) respectively: 0.5 Ba(BSCF) a NO 3 ) 2 + 0.5 Sr(BSCF) a NO 3 ) 2 + 0.8 Co(BSCF) a NO 3 ) 2 + 0.2 Fe(BSCF) a NO 3 ) 3 + 2. In order to synthesize large amounts of BSCF, expected glycine and EDTA masses were multiplied by 2.5 and 2, respectively. After EDTA dissolution, a 60 mL purple-δblack solution is obtained. At the end of the water evaporation (BSCF) a about one hour), the gelification process started. The gel was then transferred in an oven at 600°C under air atmosphere where a combustion took place 10 minutes later. Resulting ashes were kept at 600°C for one hour to remove carbon residues. Finally, ashes were manually ground and heated at 850°C for 10 hours.

FeWO 4

FeWO 4 was synthesized by a precipitation method. Two equimolar 15 mL solutions of FeCl 2 .4H 2 O (BSCF) a puriss. p.a., ≥99%) and Na 2 WO 4 .2H 2 O (BSCF) a ACS Reagent, ≥99%), both from Sigma Aldrich were prepared. Precursor mass used are listed in Tab.S2. The iron chloride solution was heated at 70°C under magnetic stirring for 10 minutes. Then, the sodium tungstate was added dropwise into the iron chloride solution leading to a brow precipitate. The resulting solution was kept at 70°C under magnetic stirring for 3 hours. The precipitate was recovered by filtration before being washed three times with distilled water and subsequently three times with ethanol.

Activated BSCF carbon

Activated carbon was purchased from ACS Material  . The particle average size is 5 µm. Activated carbon from ACS Material is mesoporous with a pore size distribution from 2 to 2.2 nm and its BET specific surface area is 2,000 m².g -δ1 .

2.2.BSCF and FeWO 4 powder characterizations

Prepared BSCF and FeWO 4 powders were characterized by X-δray diffraction using a PANalytical X'Pert in the Bragg-δBrentano configuration with CuKα radia α radiation, from 10 to 90°w ith a step angle of 0.032°. Their morphology were observed by scanning electron microscopy on a Hitachi S4800. BSCF composition was evaluated by EDS analysis.

2.3.Electrode preparation

Electrodes were prepared by mixing active materials with acetylene black (BSCF) a Alfa Aesar) and PTFE (BSCF) a 60 wt% dispersed in water, Sigma Aldrich) in ethanol. Mass ratios (BSCF) a active material: acetylene black: PTFE) were 60:30:10 for BSCF and FeWO 4 based electrodes and 75:15:10 for activated carbon based electrodes. After ethanol evaporation at 60°C under magnetic stirring, the resulting paste was repeatedly cold rolled until a homogeneous film was obtained.

A 10 mm diameter disk was cut off from the film and pressed at 10 tons onto a folded stainless steel grid. For asymmetric devices (BSCF) a Swagelok type), electrode films were pressed onto nickel foam at 10 tons. Then, a 6 mm diameter disk shape was cut off. Electrode loadings used for electrochemical tests were 3.2-δ4.0 mg carbone .cm -δ ² (BSCF) a 5.3-δ6.7 mg electrode .cm -δ ²), 4.4-δ 15.3 mg BSCF .cm -δ ² (BSCF) a 7.4-δ25.5 mg electrode .cm -δ ²) and 4.7-δ5.5 mg FeWO4 .cm -δ ² (BSCF) a 7.8-δ9.2 mg electrode .cm -δ ²).

In contrast with the 20 wt% usually used, a larger amount of acetylene black was necessary to fabricate BSCF and FeWO 4 electrodes. Only from 30 wt%, a percolation threshold was reached allowing electrodes to have a sufficient electronic conductivity for optimal performances. At lower acetylene black content, the electrochemical signature of electrodes was less capacitive and a specific capacitance twice lower was obtained [START_REF] Lannelongue | Investigation of Ba 0.5 Sr 0.5 Co x Fe 1-x O 3-δ as a pseudocapacitive electrode material with high volumetric capacitance[END_REF]. Furthermore, the specific capacitance of acetylene black in these electrodes is 1 F.g -δ1 . With respect to the measured electrode capacitances such limited contribution was neglected.

2.4.Electrochemical tests

BSCF, FeWO 4 and activated carbon -δbased electrodes were first tested in a three electrode cell with a platinum counter electrode and an Ag/AgCl reference electrode. Cyclic voltammetry was performed in 5M LiNO 3 at 5 mV.s -δ1 to determine their potential window and specific capacitance. Specific capacitances C spe,electrode BSCF (BSCF) a in F.g -δ1 ) are calculated with the following equation:

C spe , electrode = ∫ V i V f i. dV ∆V . υ . m (3) With ∫ V i V f
i . dV the voltammogramm positive part area (BSCF) a in A.s), ΔV the potential window (BSCF) a in V), υ the scan rate (BSCF) a in V.s -δ1 ) and m the active material mass (BSCF) a in g).

Asymmetric C/BSCF and FeWO 4 /BSCF device specific and volumetric performance were evaluated by cyclic voltammetry and galvanostatic cycling (BSCF) a in a current density range from 0.2 to 4 A.g -δ1 of active material in both electrodes) in a three electrode Swagelok cell with an Ag/AgCl reference electrode, in aqueous 5M LiNO 3 . Both electrodes were separated with glass microfibers separators (BSCF) a Wathman  paper). By cyclic voltammetry, the device capacitances C BSCF (BSCF) a in F), specific capacitances C spe BSCF (BSCF) a in F.g -δ1 ) and volumetric capacitances C vol BSCF (BSCF) a in F.cm -δ3 ) were calculated using equations 4, 5 and 6 respectively.

C= ∫ V i V f i. dV ∆ U .υ (4) C spe = C m'
(5)

C vol = C V (6)
Where ΔU is the device cell voltage, in V, m' is the active material mass in both electrodes in g and V is the geometrical volume of both electrodes and the geometrical volume of both nickel foam current collectors in cm 3 .

The capacitance C, the maximum energy E max BSCF (BSCF) a in Wh) and power densities P max (BSCF) a in W) were calculated from galvanostatic cycling and with equations 7, 8 and 9:

C=i.

∫

t i t f ∆ U .dt ∆ U 2 (7)
E max = 1 2 .C . ∆U 2 (8)
P max = ∆ U 2 4 . R (9)
Where i BSCF is the applied current density, ΔU is th U is the cell voltage of the device of the device and R is the equivalent series resistance (BSCF) a Ω) obtai ) obtained by ohmic drop measurement during galvanostatic cycling. Specific performance (BSCF) a and specific capacitances) were calculated by taking into account the active material mass of both electrodes (BSCF) a Eq. 5). As the specific capacitance of acetylene black used in the electrodes is less than 1 F.g -δ1 , its contribution was neglected. Volumetric performance were obtained by taking into account both electrodes and nickel foam current collector volume (BSCF) a Eq. 6). Self-δdischarge behaviors were evaluated through chronopotentiometry technique. Before this step, devices were fully galvanostatically charged and the cell were kept at their maximum cell voltage during 3 hours before letting the device self-δdischarged. Cycling ability of C/BSCF and FeWO 4 /BSCF devices was evaluated by galvanostatic cycling. All electrochemical tests were performed using a VMP3 potentiostat-δgalvanostat from Biologic running with the EC-δLab software. A 5M LiNO 3 electrolyte was used as the best specific capacitances for both BSCF and FeWO 4 electrodes were obtained in this given electrolyte. BSCF CV (BSCF) a Fig. 1a) depicts a box-δtype shape characteristic of a material with a pseudocapacitive behavior, with some distortions from the typical rectangular shape. BSCF -δ based electrode is stable from 0 to 0.8 V vs Ag/AgCl and displays a specific capacitance of 57 F.g -δ1 (BSCF) a 46 C.g -δ1 ). As such, it can be used as positive electrode material. Above 0.8 and below 0

Results and discussion

3.1.BSCF and

V vs Ag/AgCl, the current increases (BSCF) a in absolute value). This is assigned to oxygen and hydrogen evolution reactions, respectively. In the present case, the 50 th cycle is the cycle from which the CV shape and the specific capacitance does not change anymore. From the 1 st to the 50 th cycle, an increase of the specific capacitance from 30 to 57 F.g -δ1 was observed. FeWO 4 has already been studied as negative electrode material for supercapacitors. The electrode made from FeWO 4 prepared by a precipitation method is stable from -δ0.6 to 0V vs BSCF Ag/AgCl (BSCF) a Fig. 1b) and displays a specific capacitance of 60 F.g -δ1 (BSCF) a 36 C.g -δ1 ). Stable CV shape of FeWO 4 were rapidly obtained (BSCF) a 10 cycles). From the 1 st cycle to the 10 th , only a very slight change in specific capacitance was observed. The charge storage mechanism in FeWO 4 electrode involves the Fe 2+ /Fe 3+ redox couple. Potential below -δ0.7 V vs Ag/AgCl should be avoided because Fe 2+ is irreversibly reduced to Fe 0 . CV of activated carbon (BSCF) a as negative electrode) is representative of a capacitive behavior (BSCF) a Fig. 1c). This electrode can be cycled from -δ0.8 to 0 V vs Ag/AgCl. Below -δ0.8 V vs Ag/AgCl, the current increases (BSCF) a in absolute value), which suggests that the hydrogen evolution reaction begins, causing electrolyte degradation. In this potential window, its specific capacitance is 160 F.g -δ1 (BSCF) a 128 C.g -δ1 ) at 5 mV.s -δ1 . According to these tests, two types of asymmetric devices can be built. The first one, C/BSCF, is designed by associating a negative electrode made of activated carbon and a BSCF positive electrode. The second one is an all oxide device, with a negative electrode made of FeWO 4 and a BSCF positive electrode.

Asymmetric devices

To keep electrode cycling in their respective potential windows, charge balance of the device has to be ensured by using an accurate weight ratio of active materials in both electrodes (BSCF) a calculated by taking into account electrode capacities and potential windows) [START_REF] Balducci | Perspective-A Guideline for Reporting Performance Metrics with Electrochemical Capacitors: From Electrode Materials to Full Devices[END_REF]. However, since each electrode material has different capabilities upon scan rate (BSCF) a or current density), this weight ratio can only be determined for a given scan rate or a given current density. In the next section, the methodology was as followed. Firstly, weight ratios were calculated to design asymmetric devices with the aim to be cycled at 5 mV.s -δ1 (BSCF) a or corresponding current density) in 5M LiNO 3 electrolyte. These specific ratios were determined using equation (BSCF) a 10):

m +¿ m -¿ = C -¿ C +¿ ¿ ¿ ¿ ¿ (10 )
Where m + and m -δ are the active material mass in the positive and the negative electrode respectively and C + and C -δ are the capacities (BSCF) a in C.g -δ1 ) of the positive and negative electrode respectively.

After analysis of the results (BSCF) a capacitances and electrochemical stability windows of electrodes), several devices with various electrode weight ratios were designed and tested by galvanostatic cycling at various current densities with the aim to find the optimal conditions allowing a good compromise between the device performances and the electrochemical stability windows of each electrodes. In this section, from one weight ratio to another, performances are not compared at the same current density, but in conditions electrodes cycle in their respective electrochemical stability window (BSCF) a i.e. BSCF in conditions a fast degradation of the device, caused by water splitting, is avoided). The conditions, in terms of electrode weight ratios and current densities, leading to the best compromise between electrochemical stability of electrodes and performances, were used to test the longterm cycling ability and self-δ discharge behavior of the fabricated asymmetric devices.

Asymmetric C/BSCF devices

As mentioned in paragraph 3.2., specific capacities of BSCF and activated carbon (BSCF) a as negative electrode) in 5M LiNO 3 at 5 mV.s -δ1 are 46 and 128 C.g -δ1 , respectively. Thus, a theoretical BSCF/C weight ratio of 2.8 is expected to allow the electrodes to cycle in their respective stable potential windows (BSCF) a i.e. from 0 to 0.8 V vs Ag/AgCl for BSCF and from -δ0.8 to 0 V vs Ag/AgCl for activated carbon). As such, electrode loadings used to build this device with a BSCF/C weight ratio of 2.8 were 14.2 mg BSCF .cm -δ2 and 5.0 mg C .cm -δ2 .

Fig. S3 depicts C/BSCF CV from 0 to 1.6 V (BSCF) a according to the electrochemical window of each electrodes), together with those of activated carbon and BSCF electrodes. The CV shape of the full device is rectangular as expected for an electrochemical capacitor. However, as shown in Fig. S3, activated carbon and BSCF do not cycle in their respective electrochemical window. In such a case, potential windows of activated carbon and BSCF based electrodes are -δ1.0 --δ0.1 V vs BSCF Ag/AgCl and -δ0.1 -0.6 V vs Ag/AgCl, respectively. As mentioned above, at -δ 1.0 V vs Ag/AgCl, water is reduced at the carbon electrode surface and loss of performance upon cycling the cell is likely to occur because of this electrolyte degradation. Actually, the same shift in the electrode potential windows was observed when using a current density ranging from 0.1 to 4 A.g -δ1 (BSCF) a of active material). As such, the BSCF/C weight ratio of 2.8 was no longer considered for the rest of the study.

To evaluate C/BSCF performance, several devices with various BSCF/C weight ratio have then been prepared and tested. BSCF/C weight ratio were 1.5, 2.1, 2.4 and 3.6. CVs at 5 mV.s -δ 1 of the fabricated devices are reported in Fig. S4. Total mass of active material and total volume of electrodes and current collectors used to evaluate device performance are listed in Tab. S4 together with the capacitances and the specific capacitances. Despite a slight decrease for the weight ratio of 3.6, the greater the weight ratio, the greater the measured capacitance. In contrast, the greater electrode masses needed for the highest weight ratio strongly impacted on the corresponding specific capacitances, as the greater the weight ratio, the lower the specific capacitance. Looking closer at electrode CVs in Fig. S4, one can notice that electrodes were operated in their safe electrochemical window only for the device with a weight ratio of 1.5, i.e. between 0 and -δ0.8 V vs Ag/AgCl for activated carbon electrode and between 0 and +0.8 V vs Ag/AgCl for BSCF electrode. For the other devices, the activated carbon electrode potential window decreases down to -δ0.8 V vs Ag/AgCl (BSCF) a hence, BSCF electrode potential window does not reach + 0.8 V vs Ag/AgCl) which could lead to electrolyte degradation.

Energy and power densities of these devices have been determined from galvanostatic cycling by applying current densities ranging from 0.2 to 4 A.g -δ1 (BSCF) a total mass of active materials in the cell). Specific and volumetric performance are shown in Fig. 2a and2b, respectively, as well as the Ragone plots. The corresponding galvanostatic cycles are depicted in Fig. S5. As generally observed for electrochemical capacitors, the energy density of fabricated C/BSCF devices decreased as the applied current density increased. At low current density, i.e. 0.2 A.g -δ 1 , the greater the BSCF/C weight ratio, the lower the energy and the power densities (BSCF) a both specific and volumetric). This behavior was assigned to both lower capacitances and greater electrode masses and volumes as the BSCF/C weight ratio increased. At 0.2 A.g -δ1 , the C/BSCF device with a weight ratio of 1.5 presented the greatest energy densities in the series at 8.6 Wh.kg -δ1 and 2.7 Wh.L -δ1 . A similar trend was observed for power densities. At 0.2 A.g -δ1 , power densities ranged from 5.6 to 3 kW.kg -δ1 and from 1.8 to 1.4 kW.L -δ1 , depending on the BSCF/C weight ratio. With the increase of the current density at 4 A.g -δ1 , the C/BSCF device with a weight ratio of 2.1 showed the greatest energy densities with 3.7 Wh.kg -δ1 and 1.3

Wh.L -δ1 . Compared to the device with a 1.5 weight ratio, this energy density improvement originated from a greater capacitance (BSCF) a 37 mF for a ratio of 2.1 vs 27 mF for a ratio of 1.5) which allowed to compensate for the larger mass and volume of the electrodes. However, power densities at the highest current density followed the same trend as 0.2 A.g -δ1 . Power densities decreased from 8.9 to 4.4 Wh.kg -δ1 and from 2.8 to 1.9 Wh.L -δ1 when the weight ratio increases.

Fig. 2.

Ragone plots representing the evolution of the power density vs the energy density of the four C/BSCF devices tested in 5M LiNO 3 with BSCF/C ratios of 1.5 (BSCF) a black), 2.1 (BSCF) a red), 2.4 (BSCF) a blue) and 3.6 (BSCF) a green). Current densities applied are 0.2, 0.5, 0.6, 0.8, 1.0, 1.2, 2.0 and 4 A.g -δ1 . Graph a) specific power and energy densities and b) volumetric power and energy densities; gravimetric values are expressed per total active weights in both electrodes and volumetric values per volume of both electrodes and their current collector. Calculations have been done using Eqs (BSCF) a 9) and (BSCF) a 10).

In the whole range of applied current densities, only a single current density applied for each C/BSCF device allows to operate BSCF and C electrodes in their safe electrochemical window. These are 0.2, 0.5, 0.5 and 1.2 A.g -δ1 for C/BSCF devices with weight ratio of 1. weight ratio allows to reach greater charge and discharge rates. To fabricate the most performing C/BSCF device, a BSCF/C weight ratio of 1.5 and a 0.2 A.g -δ1 current density should be considered. However, in these conditions, a large discrepancy between charge and discharge times is observed. To avoid this unbalanced characteristic, the device with a weight ratio of 2.1 operated at a current density of 0.5 A.g -δ1 was selected for further tests. To move a step forward in the device characterization, self-δdischarge measurements and cycling ability tests were performed on a C/BSCF device with a weight ratio of 2.1 at 0.5 A.g -δ1 , and are presented in section 3.3.3.

Tab. 1.Specific energy and power densities (BSCF) a E spe and P spe ), volumetric energy and power densities (BSCF) a E vol and P vol ) of C/BSCF full devices with BSCF/C weight ratio of 1.5, 2.1, 2.4 and 3.6 recorded in 5M LiNO 3 at 0.2, 0.5, 0.5 and 1.2 A.g -δ1 , respectively; gravimetric values are expressed per total active weights in both electrodes and volumetric values per volume of both electrodes and their current collector.

BSCF/C

Weight specific capacitances are found to remain the same, close to 16-δ17 F.g -δ1 . The potential window of BSCF electrode, ranging approximately from 0 -0.7 V vs Ag/AgCl, was fitting in its electrochemical stability window (BSCF) a 0 -0.8 V vs Ag/AgCl). However, the potential window of FeWO 4 electrodes ranged approximately from -δ0.7 -0 V vs Ag/AgCl. This potential window could result in a fade of performance upon cycling since, at the lowest limit, the electrode potential is very close to that of the irreversible Fe 2+ → Fe 0 reduction reaction. To optimize the operating conditions for FeWO 4 /BSCF devices and to evaluate their performance, galvanostatic cycling was performed at various current densities from 0.25 to 4

A.g -δ1 . Specific and volumetric densities are reported in Fig. 4 and the galvanostatic cycles are depicted in Fig. S7. Performance of the FeWO 4 /BSCF device with a weight ratio of 0.8 are not reported because, whatever the applied current density, the FeWO 4 electrode potential always reached potentials below -δ0.7 V vs Ag/AgCl. As such, poor coulombic efficiencies at 42 (BSCF) a at 0.25 A.g -δ1 ) and 92 %(BSCF) a at 4 A.g -δ1 ) were obtained, demonstrating the limited reversibility of charge and discharge processes that could originate from an irreversible reduction of Fe 2+ to Fe 0 . As for C/BSCF devices, when the current density was greater, the corresponding energy density of FeWO 4 /BSCF devices decreased, either with FeWO 4 /BSCF weight ratio at 1.67 or 2. Specific and volumetric performance of the tested FeWO 4 /BSCF devices were approximately the same but energy densities of the device with a weight ratio of 2 were slightly weaker. At 0.25 A.g -δ1 , energy densities of FeWO 4 /BSCF devices with a ratio of 1.67 and 2 were 2.9 and 2.7 Wh.kg -δ1 respectively, and 1.2 and 1.1 Wh.L -δ1 respectively. At the same current density, power densities for both devices were similar at about 3.8 kW.kg -δ1 and 1.5 kW.L -δ1 . When the current density is increased to 4 A.g -δ1 , energy densities of the devices with a ratio of 1.67 and 2 decreased to 1.1 and 1.0 Wh.kg -δ1 , respectively and to 0.5 and 0.4 Wh.L -δ1 , respectively. With these asymmetric devices, the limit of the FeWO 4 electrode potential window was lower than the expected value at -δ0.6 V vs Ag/AgCl. For each devices, a single current density allowed to limit the FeWO 4 electrode potential above -δ0.7 V vs Ag/AgCl, thus limiting the Fe 2+ reduction to Fe 0 . These current densities are 0.4 and 0.25 A.g -δ1 of active material for FeWO 4 /BSCF devices with weight ratio of 1.67 and 2, respectively (BSCF) a corresponding galvanostatic cycles are in Fig. S8). At such current densities, the devices showed the same energy densities of 2.7 Wh.kg -δ1 and 1.1 Wh.L -δ1 . The FeWO 4 /BSCF cycling ability and self-δdischarge behavior were further evaluated on the device with a FeWO 4 /BSCF weight ratio of 2 operated at 0.25 A.g -δ1 . Evolutions of the specific capacitance of these devices vs number of cycles are depicted in Fig. 5. The specific capacitance of the C/BSCF device was 17 F.g -δ1 at the beginning of the cycling test, as shown in Fig. 5a. First, the specific capacitance increases which is due to BSCF electrode activation. Then, it progressively decreased down to 15 F.g -δ1 for the 10,000 th cycle for an overall 12 % fading. This capacitance fading of the device could be due to the BSCF electrode behavior, as it showed a specific capacitance fading of approximately 10% over 2,000 cycles [30 ], whereas activated carbon electrodes are known to be stable over hundred thousands of cycles, eventually. Furthermore, coulombic efficiency of the device was above 98 % over the entire cycling test, demonstrating the good charge/discharge reversibility of the device. To go further, impedance spectroscopy was performed after the 10 th and the last cycle of the long term cycling test. Corresponding Nyquist diagrams are shown in Fig. S9a.

The resistance measured at high frequencies, at the intercept between the EIS plot and the Z' axis, corresponds to the resistance of the separators impregnated by the electrolyte. This resistance is approximately 1 Ω) obtai after the 10 th cycle and does not seem to further increase after the 10,000 th cycle. At lower frequencies a semi-δcircle can be observed. It is usually assigned to the interface resistance between the active material and current collector [START_REF] Soeda | Outstanding features of alginatebased gel electrolyte with ionic liquid for electric double layer capacitors[END_REF]. This charge transfer resistance (BSCF) a 0.8 Ω) obtai ) showed limited changes upon cycling. It only increased up to 1 Ω) obtai from the 10 th to the 10,000 th cycle. The equivalent series resistance evaluated at high frequency was 2.7 Ω) obtai after 10 cycles and increased at 3 Ω) obtai after 10,000 cycles. The limited changes upon cycling of the various resistances measured demonstrate the high stability of the device.

Cycling ability of the FeWO 4 /BSCF device has been evaluated over 45,000 cycles. The choice to apply for a greater number of cycles for this specific device was motivated by the opportunity to evaluate the cycling ability of an all-δoxide device as only a few studies depict such performance over such a large number of cycles. Changes in the specific capacitance of the FeWO 4 /BSCF device upon charge/discharge cycling at 0.25 A.g -δ1 is shown in Fig. 5b. Its initial specific capacitance at 12 F.g -δ1 goes down to 10 F.g -δ1 at the end of the cycling test, corresponding to an overall 17% fading of the specific capacitance after 45,000 cycles. In comparison with the C/BSCF device, operated at 0.5 A.g -δ1 , the specific capacitance fading of the FeWO 4 /BSCF device is limited to about 3% after the 10,000 th cycle, demonstrating the remarkable cycling ability of this device, especially when operated at a moderate current density of 0.25 A.g -δ1 . As it can be observed on this graph, the capacitance fading is more pronounced after 22,000 cycles. This behavior is not necessarily assigned to the electrodes but to a non-δoptimized setup. The Coulombic efficiency of this device upon the entire cycling test is about 95%, lower than for C/BSCF or what is generally observed in electrochemical capacitors (BSCF) a 98-δ99%). This can be due to some parasitic Fe 2+ reduction reaction to Fe 0 because of a potential limit of FeWO 4 electrode close to -δ0.7 V vs Ag/AgCl. Nyquist diagrams after 10 cycles and 45,000 cycles are depicted in Fig. S9b. The resistance measured at high frequencies increased from 1.3 to 1.7 Ω) obtai after the 45,000 th cycle. The semi-δcircle assigned to the charge transfer resistance is not clearly defined after 45,000 cycles, but, it is clear that this resistance was increased upon cycling. Finally, the equivalent series resistance also increased during cycling, from 7.4 to 18.3 Ω) obtai .

In the literature, only a few studies deal with long term stability evaluation of symmetric or asymmetric aqueous devices with at least one pseudocapacitive oxide. Among them, asymmetric devices were reported with a negative activated carbon electrode such as structure. Initial C/BSCF device capacitance faded down by 12% over 10,000 cycles (BSCF) a 0.5 A.g -δ 1 , 1.6 V, 5M LiNO 3 ) while it was 17% fading for the FeWO 4 /BSCF device over 45,000 cycles (BSCF) a 0.25 A.g -δ1 , 1.4 V, 5M LiNO 3 ). This cycling ability, similar to that of FeWO 4 /MnO 2 , originates from the good cycling stability of individual electrodes.

Conclusion

We report for the first time, two asymmetric electrochemical capacitors based on BSCF positive electrode material. The first one includes an activated carbon based negative electrode. The second, a FeWO 4 -δbased negative electrode, leading to a device with two high density multicationic oxides as electrode materials. The high densities of both oxides, together with the low capacitances of the electrodes led to lower specific performance than those of a symmetrical C/C device. However, the high densities of BSCF and FeWO 4 enable electrodes of smaller volume. On one hand, the small volume of electrodes was not sufficient to compensate the limited capacitance of the FeWO 4 /BSCF device. On the other hand, the high density of BSCF, associated to the high capacitance of activated carbon electrode led to similar volumetric energy density as for the C/C devices, despite a limited capacitance. At low current density (BSCF) a 0.2-δ0.4 A.g -δ1 ), the C/BSCF device volumetric energy density was even greater than that of the C/C device, at 2.3 Wh.L -δ1 (BSCF) a relative to the volume of electrodes and current collectors). Furthermore, both devices presented attractive cycling abilities upon cycling with a capacitance retention of 88% over 10,000 cycles for the C/BSCF device and 83% over 45,000 cycles for the FeWO 4 /BSCF device. It is important to notice that such a long cycling test of an asymmetric device built on two pseudocapacitive oxides is scarce in the literature. Furthermore, asymmetric devices present better self-δdischarge characteristics than the C/C device. Asymmetric devices built on two pseudocapacitive multicationic oxides could be an attractive strategy to improve the volumetric energy density of electrochemical capacitors. However, in aqueous based electrolytes, large specific capacitances are mandatory to compete with symmetric C/C devices, at least 100 F.g -δ1 .

  [1,3]. Such behavior has been observed for various electrode materials including metal oxides such as RuO 2 [4-6 ], MnO 2 [7-9 ], Fe 3 O 4 [10,11], but also nitrides such as VN [12,13] and Mo x N [14 ], conducting polymers [15 ] or Mxenes [16 ]. Thanks to their high density compared to that of activated carbon, pseudocapacitive oxides are attractive materials to improve the volumetric energy density of electrochemical capacitors. As such, Goubard-δBretesché et al. predicted a volumetric energy density of a symmetrical electrochemical capacitor MnO 2 /MnO 2 (BSCF) a bulk density: 4.5 g.cm -δ3 )

[ 18 ]

 18 . Among them, ABO 3 perovskite materials [19-23 ], AB 2 O 4 spinel materials [24-27 ], MWO 4 tungstate materials [28 ] or A 2 B 2 O 7 pyrochlore materials [29 ] have been considered.

  FeWO 4 powder characterizations BSCF and FeWO 4 XRD patterns are shown in Fig. S1. BSCF XRD pattern is characteristic of a perovskite structure with the expected Pm-δ3m space group. BSCF XRD pattern is similar to those of previous studies where BSCF was prepared by various sol-δgel synthesis [32-36 ], including the glycine-δnitrate process [32 ], and by solid state reaction [35 ], which all needed a minimum calcination temperature of 900°C. FeWO 4 XRD pattern shows broad peaks of low intensities, characteristic of the poor crystallinity of FeWO 4 prepared by precipitation method. FeWO 4 XRD pattern is different of those of FeWO 4 prepared by hydrothermal synthesis of polyol-δmediated synthesis which allowed to prepare crystalline particles because a minimum annealed temperature of 180°C was used [28,37]. In our case, the temperature used from the beginning to the end of the synthesis is 70°C and the XRD pattern is similar to the one of NiWO 4 prepared by the same route [38 ]. EDS analysis of BSCF powder showed that the atomic ratio Ba/Sr is close to 1. Furthermore, the atomic percentage of Co in the B site of the perovskite is 80%. Finally, the atomic ratio (BSCF) a Ba+Sr)/(BSCF) a Co+Fe) is close to 1 (BSCF) a see Tab. S3). The overall chemical composition is thus confirmed for the prepared BSCF. SEM pictures of BSCF and FeWO 4 powders are depicted in Fig. S2. BSCF prepared powder is composed of 5-δ 20 µm particles whereas FeWO 4 SEM micrography shows that the powder is composed of 20-δ 40 nm particles. 3.2.Electrochemical tests with BSCF, FeWO 4 and activated carbon electrodes In Fig. 1 are shown the cyclic voltammograms (BSCF) a CVs) of BSCF (BSCF) a 50 th cycle), FeWO 4 (BSCF) a 10 th cycle) and activated carbon (BSCF) a 10 th cycle) based electrodes, recorded in 5M LiNO 3 at 5 mV.s -δ1 .

Fig. 1 .

 1 Fig. 1.CVs recorded at 5 mV.s -δ1 in aqueous 5M LiNO 3 of a) BSCF based electrode (BSCF) a 50 th cycle), b) FeWO 4 based electrode (BSCF) a 10 th cycle) and c) activated carbon electrode (BSCF) a 10 th cycle); gravimetric values are expressed per active weight in electrodes.

Fig. 3 .

 3 Fig. 3. Total active material mass, total volume of electrodes and current collectors, capacitances and specific capacitances of fabricated devices are listed in Tab. S5. As for C/BSCF devices, the CV of FeWO 4 /BSCF device shows a distorted rectangular shape, characteristic of a pseudocapacitive behavior. From FeWO 4 /BSCF weight ratio at 0.8 to 2,

Fig. 3 .

 3 Fig. 3.CVs recorded at 5 mV.s -δ1 in 5M LiNO 3 of FeWO 4 /BSCF devices (BSCF) a black line) together with FeWO 4 (BSCF) a green dots) and BSCF electrodes (BSCF) a green line) CVs with BSCF/FeWO 4 weight ratio of a) 0.8, b) 1.67 and c) 2; gravimetric values are expressed per active weight in both electrodes.

Fig. 4 .

 4 Fig. 4.Ragone plots representing the evolution of the power density vs the energy density of the two FeWO 4 /BSCF devices tested in 5M LiNO 3 with BSCF/FeWO 4 ratio of 1.67 (BSCF) a black) and 2 (BSCF) a red). Current densities applied are 0.25, 0.4, 0.5, 0.6, 0.8, 1, 1.2 and 4 A.g -δ1 . Graph a) represents specific power and energy densities and b) represents volumetric power and energy densities; gravimetric values are expressed per total active weights in both electrodes and volumetric values per volume of both electrodes and their current collector. Calculations have been done using Eqs (BSCF) a 9) and (BSCF) a 10).

Fig. 5 . 6 .

 56 Fig. 5.Cycling ability test performed on a) C/BSCF device with a BSCF/C ratio of 2.1 at 0.5 A.g -δ1 in 5M LiNO 3 (BSCF) a evolution of the specific capacitance in black and coulombic efficiency in blue) and b) FeWO 4 /BSCF device with a BSCF/FeWO 4 weight ratio of 2 at 0.25 A.g -δ1 in 5M LiNO 3 (BSCF) a evolution of the specific capacitance in black and coulombic efficiency in green). Insets are galvanostatic cycles after various cycles; gravimetric values are expressed per total active weights in both electrodes.

Fig. 6 .

 6 Fig. 6.Self-δ discharge profile of C/C, C/BSCF and FeWO 4 /BSCF devices.

  Ba 0.5 Sr 0.5 Co 0.8 Fe 0.2 O 3 + 4.8 CO 2 + 3.84 H 2 O + 2.58 N 2

	13 HOOC-δCH 2 -δNH 2
	↓	(1)
	Ba 0.5 Sr 0.5 Co 0.8 Fe 0.2 O 3 + 4.26 CO 2 + 5.33 H 2 O + 3.165 N 2
	0.5 Ba(BSCF) a NO 3 ) 2 + 0.5 Sr(BSCF) a NO 3 ) 2 + 0.8 Co(BSCF) a NO 3 ) 2 + 0.2 Fe(BSCF) a NO 3 ) 3 + 0.48 C 10 H 16 N 2 O 8
	↓	(2)

  Potential ranges of activated carbon and BSCF electrodes at such optimized current densities are -δ0.8 -0 V vs Ag/AgCl and 0 -0.8 V vs Ag/AgCl, respectively, corresponding to targeted electrochemical stability windows of both electrodes. For lower current densities, activated carbon electrode potential goes below -δ0.8 V vs Ag/AgCl and for higher current densities, BSCF electrode potential rises to 0.8 V vs Ag/AgCl and above. According to Tab. 1, increasing the BSCF/C

5, 2.1, 2.4 and 3.6, respectively. Respective galvanostatic cycles at such current densities are shown in Fig. S6 and corresponding performance are reported in Tab. 1.

  The study on all oxide asymmetric FeWO 4 /BSCF devices followed the same methodology as for C/BSCF devices. According to specific capacities measured for FeWO 4 and BSCF electrodes, respectively 36 and 46 C.g -δ1 at 5 mV.s -δ1 in 5M LiNO 3 , a FeWO 4 /BSCF weight ratio of 0.8 should lead to suitable potential windows for both electrodes. Alternatively, two other devices with FeWO 4 /BSCF weight ratio at 1.67 and 2 were tested. These devices have been cycled between 0 and 1.4 V.

	3.3.2. Asymmetric FeWO 4 /BSCF devices
		E spe	P spe	E vol	P vol
	ratio	Wh.kg -1	kW.kg -1	Wh.L -1	kW.L -1
	1.5	8.6	5.5	2.7	1.7
	2.1	6.5	5.3	2.3	1.9
	2.4	4.5	3.8	1.9	1.6
	3.6	3.9	3.9	1.8	1.8

CVs of the various FeWO 4 /BSCF device, together with those of their electrodes, are shown in

  FeWO 4 /MnO 2 device had a 84% retention over 40,000 cycles (BSCF) a 20 mV.s -δ1 , 1.6 V, 5M LiNO 3 ) [31 ]. As MnO 2 electrode has demonstrated a fair cycling stability, the greater cycling ability of the FeWO 4 /MnO 2 device when compared to that of Fe 3 O 4 /MnO 2 device was assigned to the stability of the Fe 2+ /Fe 3+ redox couple in the FeWO 4

	C/BiMn 2 O 5 [41 ] and C/MnO 2 [42 ]. The first one presented only a 90% retention of its
	capacitance over 1,000 cycles (BSCF) a 10 mA.cm -δ2 , 1.8 V, 0.5M Na 2 SO 4 ). On the other hand, the
	C/MnO 2 device presented the greatest cycling ability ever reported in the literature with a
	87.5% of retention over 195,000 cycles (BSCF) a 40 mA.cm -δ2 , 2 V, 0.1M Kα radia 2 SO 4 ). Some symmetric
	devices have also been tested, such as ZnFe 2 O 4 /ZnFe 2 O 4 (BSCF) a composite electrodes with carbon
	nanotubes) which maintained only 70 % of its capacitance over 2,000 cycles (BSCF) a 0.9 V, 1M LiCl)
	[43 ]. Finally, a few studies on asymmetric devices free of activated carbon have been
	reported. For example, VN/MnO 2 (BSCF) a composite electrodes with carbon nanotubes) retained only
	80% of its initial capacitance over 1,000 cycles (BSCF) a 10 mA, 1.8 V, 0.5M Na 2 SO 4 ) [44 ]. The first
	asymmetric device with two oxides ever reported, Fe 3 O 4 /MnO 2 , presented also a limited

cycling ability with a 50% capacitance fading over 5,000 cycles (BSCF) a 1.8 V, 0.1M Kα radia 2 SO 4 )

[START_REF] Brousse | A Hybrid Fe 3 O 4 /MnO 2 Capacitor in Mild Aqueous Electrolyte[END_REF]

. As a comparison with this latter device,

Acknowledgements

This work was supported by the French National Agency through IVEDS project -δ Improving the Volumetric Energy Density of Supercapacitors -ref ANR-δ15-δCE05-δ0011.

Notes

The authors declare no competing financial interest


Mélanie Leroy

Maxime Bertoux

Emilie Skrobala

Elisa Mode

Catherine Adnet-Bonte

Isabelle Le Ber

Stéphanie Bombois

Pascaline Cassagnaud

Yaohua Chen

Vincent Deramecourt

Florence Lebert

Marie Anne Mackowiak

Adeline Rollin Sillaire

Marielle Wathelet

Florence Pasquier

Thibaud Lebouvier
email: lebouvierthibaud.lebouvier@chru-lille.fr

Dr Abied Rachid

Dr Adnet Cathrine

Dr Barois Arnaud

Dr Baude Stéphanie

Dr Berriot Véronique

Dr Bombois Stéphanie

Dr Boyer Gloria

Dr Brique Didier

Dr Calais Gauthier

Dr Cassagnaud Pascaline

Dr Drchekroud Hacène

Dr CLICHE Joel Chen Yaohua

Dr Crinquette Charlotte

Dr Dachy Valérie

Dr Debock Valerie

Dr Deprez Anne

Pr Deramecourt Vincent

Dr Dereeper Olivier

Dr Devos Philippe

Dr Elazouzi Abdelghani

Dr Fanjaud Nicolas

Dr Forzy Pierre

Dr Gallouj Karim

Dr Garcon Karine

Dr Honore Marie

Dr Huvent Dominique

Dr Idiri Houria

Dr Ladeiro Annabelle

Dr Lebert Florence

Dr Lebouvier Thibaud

Dr Le Coz Patrick

Dr Leclercq Eugénie

Dr Lefebvre Denis

Dr Maciejasz Pierre

Dr Messin Rémi

Pr Pasquier Florence

Dr Petit Valérie

Dr Ponthieu Sandrine

Dr Quievre Cécile

Dr Roche Jean

Dr Rollin Sillaire

Dr Rosolacci Thierry

Dr TAILLEZ Senechal Olivier

Dr Tison Frédéric

Dr Tollot Sarah

Dr Trocmet Marie

Dr Verpoort Charlotte

Characteristics and progression of patients with frontotemporal dementia in a regional memory clinic network

Keywords: Frontotemporal dementia, epidemiology, progression, dementia

Abstract

Background

Due to heterogeneous clinical presentation, difficult differential diagnosis with Alzheimer's disease (AD) and psychiatric disorders, and evolving clinical criteria, the epidemiology and natural history of frontotemporal lobar degeneration (FTD) remain elusive. In order to better characterize FTD patients we relied on the database of a regional memory clinic network with standardized diagnostic procedures and chose AD patients as a comparator.

Methods

Patients that were first referred to our network between January 2010 and December 2016 and whose last clinical diagnosis was degenerative or vascular dementia were included. Comparisons were conducted between FTD and AD as well as between the different FTD syndromes, divided into language variants (lvFTD), behavioral variant (bvFTD) and FTD with primarily motor symptoms (mFTD). Cognitive progression was estimated with the yearly decline in Mini Mental State Examination (MMSE).

Results

Among the patients that were referred to our network in the six-year time span, 690 were ultimately diagnosed with FTD and 18,831 with AD. Patients with FTD syndromes represented 2.6% of all-cause dementias. The age-standardized incidence was 2.90 per 100 000 person-year and incidence peaked between 75 and 79 years. Compared to AD, patients with FTD syndromes had a longer referral delay and delay to diagnosis. Patients with FTD syndromes had a higher MMSE score than AD at first referral while their progression was similar. mFTD patients had the shortest survival while survival in bvFTD, lvFTD and AD did not significantly differ. FTD patients, especially those with the behavioral variant, received more antidepressants, anxiolytics and antipsychotics than AD patients.

Conclusions

FTD syndromes differ with AD in characteristics at baseline, progression rate and treatment. Despite a broad use of the new diagnostic criteria in an organized memory clinic network, FTD syndromes are longer to diagnose and account for a low proportion of dementia cases, suggesting persistent underdiagnosis. Congruent with recent publications, the late peak of incidence warns against considering FTD as being exclusively a young-onset dementia.

Background

Frontotemporal lobar degeneration (FTD) is the second leading cause of early-onset dementia after Alzheimer's disease (AD) [START_REF] Ratnavalli | The prevalence of frontotemporal dementia[END_REF]. FTD is characterized by changes in behaviour and/or language due to the relatively selective atrophy of the frontal and temporal lobes [START_REF] Lashley | Review: an update on clinical, genetic and pathological aspects of frontotemporal lobar degenerations[END_REF]. In the past decade, the nosology of FTD has evolved outstandingly, prompting changes in diagnostic criteria. There are three main clinical presentations of FTD. The behavioural variant of FTD (bvFTD) is defined by an early and prominent behavioural and dysexecutive syndrome, whose core symptoms were revised by Rascovsky et al. in 2011 [START_REF] Rascovsky | Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia[END_REF]. The two language variants of FTD (lvFTD) include the semantic and non-fluent presentations of primary progressive aphasia (PPA), also defined by updated clinical criteria [START_REF] Gorno-Tempini | Classification of primary progressive aphasia and its variants[END_REF]. In addition, FTD can initially present with motor symptoms (mFTD) such as features of atypical parkinsonism (progressive supranuclear palsy [PSP] and corticobasal syndrome [CBS]) [START_REF] Höglinger | Clinical diagnosis of progressive supranuclear palsy: The movement disorder society criteria. Movement disorders : official journal of the Movement[END_REF].

Although being an umbrella term underlain by >20 different possible pathologies [START_REF] Josephs | Neuropathological background of phenotypical variability in frontotemporal dementia[END_REF], FTD stands as a unifying entity because of the lack of correlations between FTD syndromes and pathology [START_REF] Kertesz | The evolution and pathology of frontotemporal dementia[END_REF]. bvFTD, for example, can be underlain by tau, TDP-43 or rarer pathologies, and on the contrary, one single pathology, such as PSP, can manifest with several clinical syndromes [START_REF] Josephs | Neuropathological background of phenotypical variability in frontotemporal dementia[END_REF]. One exception to the unpredictability of the underlying pathology is the identification of a causal genetic mutation. Patients with FTD syndromes have a positive family history in 26-31% [START_REF] Greaves | An update on genetic frontotemporal dementia[END_REF], highlighting the importance of genetics.

The most common FTD mutations, all linked to a specific pathology, are found on MAPT, PGRN and C9ORF72 genes [START_REF] Greaves | An update on genetic frontotemporal dementia[END_REF].

FTD prevalence was estimated between 0.01-4.61 per 1,000 person and the incidence between 0.01-2.5 per 1,000 person/year [START_REF] Hogan | The Prevalence and Incidence of Frontotemporal Dementia: a Systematic Review[END_REF]. In recent dementia cohorts, FTD cases have been found to account for 1.6 to 7% of dementia cases [START_REF] Religa | the Swedish Dementia Registry -a tool for improving the quality of diagnostics, treatment and care of dementia patients in clinical practice[END_REF][START_REF] Van Der Flier | Amsterdam Dementia Cohort: Performing Research to Optimize Care[END_REF]. However, those figures need to be considered with caution. First, FTD is still underdiagnosed: neuropathological studies performed in communities where brain donation reaches a high level of acceptance show that as much as 5-9 % of the elderly population with or without cognitive impairment at death have FTD pathology [START_REF] Barker | Relative Frequencies of Alzheimer Disease, Lewy Body, Vascular and Frontotemporal Dementia, and Hippocampal Sclerosis in the State of Florida Brain Bank[END_REF][START_REF] Beach | Arizona Study of Aging and Neurodegenerative Disorders and Brain and Body Donation Program[END_REF]. It has been previously estimated that about 40% of FTD are misdiagnosed [START_REF] Rosso | Frontotemporal dementia in The Netherlands: patient characteristics and prevalence estimates from a population-based study[END_REF] and time to diagnosis is longer than for other dementias [START_REF] Van De Vliet | Time to diagnosis in young-onset dementia as compared with lateonset dementia[END_REF][START_REF] Zhao | Delayed help seeking behavior in dementia care: preliminary findings from the Clinical Pathway for Alzheimer's Disease in China (CPAD) study[END_REF].

Second, with some exceptions [START_REF] Coyle-Gilchrist | Prevalence, characteristics, and survival of frontotemporal lobar degeneration syndromes[END_REF], most past estimations have been done using the previous Lund and Manchester [START_REF]Clinical and neuropathological criteria for frontotemporal dementia. The Lund and Manchester Groups[END_REF] or Neary criteria [START_REF] Neary | Frontotemporal lobar degeneration[END_REF]. Yet the revised clinical criteria and the addition of new syndromes to the FTD spectrum outdate previous publications. Third, advances in neuropsychology, neuroimaging and cerebrospinal fluid (CSF) biomarkers and genetics have improved FTD diagnosis in challenging situations such as psychiatric, amnestic or late-onset presentations of the disease [START_REF] Bertoux | Two distinct amnesic profiles in behavioral variant frontotemporal dementia[END_REF][START_REF] Ducharme | Clinical Approach to the Differential Diagnosis Between Behavioral Variant Frontotemporal Dementia and Primary Psychiatric Disorders[END_REF][START_REF] Jack | Suspected non-Alzheimer disease pathophysiology--concept and controversy[END_REF].

However, beyond research purposes, whether improving FTD diagnosis at the population level would stand a cost-benefit analysis is a subject that should be addressed open-mindedly. Indeed, one could argue that differential dementia diagnosis workup is a costly venture [START_REF] Winblad | Defeating Alzheimer's disease and other dementias: a priority for European science and society[END_REF] that can be questioned in the absence of disease-modifying treatments. The demonstration that FTD diagnosis is associated with different prognoses and therapeutic approaches in routine care would advocate against a symptomatic approach of dementia. Thus, data sharing on current FTD diagnoses and management is needed. We undertook the present study in a large regional memory clinic (MC) network to get a better overview of the incidence, characteristics and natural history of FTD syndromes defined using recent diagnostic criteria. The objectives were to study the characteristics of the FTD patients referred to the network from January 2010 to December 2016, including age at onset, time to diagnosis, clinical presentations, cognitive progression and treatment.

Patients and methods

Patient selection

Founded in 1993, the Méotis network is the first French MC network, involving 30 MCs in the French Nord and Pas-de-Calais departments, sharing data within a common patient database since 1997.

Meotis database reached a caseload of over 104 000 patients in 2018, representing more than 350 000 visits [START_REF] Chen | Twenty-year trends in patient referrals throughout the creation and development of a regional memory clinic network[END_REF]. In all MCs, a multidisciplinary assessment is performed by neurologists, geriatricians, psychologists, dedicated nurses and social workers; whenever necessary, patients can be assessed by psychiatrists, speech therapists and dedicated nurses. Diagnostic work-up is harmonized throughout the network, and standardized data on patient characteristics and healthcare activity are systematically collected. All harmonized data are monitored and computerized by a data manager in the tertiary-referral Memory Resources and Research Center (MRRC) of the Lille University Hospital.

We included patients that were referred for the first time to one of the network's MC from January 2010

to December 2016, and whose last clinical diagnosis during the follow-up was FTD, AD or other causes of dementia. We first extracted all dementia cases to calculate the respective proportions of AD and FTD syndromes. Then we focused on the subpopulation of AD and FTD syndromes for systematic comparisons. Since AD is the dominant cause of dementia, AD patients were chosen as a comparator.

Data extraction was performed on September 2019, 33 months after the end of the inclusion period. For the few patients that received a diagnosis of bvFTD and lvFTD before the new criteria were published and were not followed up beyond 2011, we checked retrospectively that they fulfilled the revised diagnostic criteria. The bvFTD group comprised pure bvFTD [START_REF] Rascovsky | Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia[END_REF], and a minority of patients with associated amyotrophic lateral sclerosis. The lvFTD group included a semantic and non-fluent agrammatic PPA [START_REF] Gorno-Tempini | Classification of primary progressive aphasia and its variants[END_REF] as well as rarer PPA variant such as apraxia of speech. The mFTD group comprised the PSP [START_REF] Litvan | Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome): Report of the NINDS-SPSP International Workshop[END_REF] and CBS [START_REF] Armstrong | Criteria for the diagnosis of corticobasal degeneration[END_REF] patients. Patients with overt motor neurone disease at presentation are usually not referred to our network because of a specialized regional amyotrophic lateral sclerosis care pathway.

Data collection

We extracted the following data from the Méotis database: sex, age at first referral, referral delay, age at diagnosis, symptoms onset and diagnostic procedures. We collected the Mini Mental State Examination (MMSE) [START_REF] Folstein | Mini-mental state". A practical method for grading the cognitive state of patients for the clinician[END_REF] and the short 4-item Instrumental Activities of Daily Living (IADL-4) [START_REF] Pérès | Natural history of decline in instrumental activities of daily living performance over the 10 years preceding the clinical diagnosis of dementia: a prospective population-based study[END_REF] scores at first referral. In this article IADLs score was calculated by summing up the number of maintained activities (ranging from 0 (full dependence) to 4 (complete autonomy). The referral delay was defined as the interval, expressed in months, between symptoms onset (declared by the patient and caregiver) and first referral to the network. The clinical follow up was defined as the interval, expressed in years, between the first and the last visit within the network. The survival was defined as the interval, expressed in years, between disease onset and death. Drug treatment was recorded at every visit. A patient was considered under a specific drug treatment if it was recorded at least once during follow up.

Only the last clinical diagnosis was considered in this study because of its higher accuracy. The last diagnosis was the one made or kept after all diagnostic procedures and retained at follow-up. Diagnosis wandering was defined as the time from first referral to the last retained clinical diagnosis.

The date of death was retrieved from the National Institute of Statistics and Economic Studies (French: Institut national de la statistique et des études économiques) national death database thanks to the MatchID tool (https://deces.matchid.io/) on September 2020

The datasets considered in the current study are available from the corresponding author on reasonable request. The database was declared to the ad hoc commission (Commission Nationale Informatique et Libertés (CNIL)) protecting personal data (#2146189V1). Privacy and confidentiality rules were respected.

Statistical Analysis

Quantitative variables were described by the mean and standard deviation if the distribution was normal, or by the median and interquartile range otherwise. Qualitative variables were described by the numbers and percentages of each modality.

Diagnostic subtypes (bvFTD, FTD mFTD and AD) were described and compared across all parameters.

Quantitative variables were analyzed by an ANOVA or the Kruskal-Wallis non-parametric equivalent.

Qualitative variables were compared by an exact Chi-square or Fisher's test (in the case of a theoretical number of cases below 5). A Bonferroni correction was applied to post-hoc comparisons of the FTD subgroups with respect to the AD group. The effect size was calculated as the standardized mean difference (for quantitative variables) and the Cramer's V coefficient (for qualitative variables). A mixed linear model analyzed the evolution of the MMSE over time. The factors introduced into the model were time, diagnosis and the interaction between diagnosis and time.

Incidence rates were calculated as the number of incident cases divided by the total number of personyears (py) for the catchment area over the 7 years. All rates were calculated using the reference population of the corresponding geographic area estimated by the French National Institute of Demographic Research (INED) on January 2015, as population at risk. Therefore, no variation was assumed during the 7 years of the study period. Age-standardized rates were calculated using the Revised European Standard Population 2013 (ESP2013). Results were presented in cases per 100,000 person-years. Concerning mortality, median survival time after diagnosis was calculated for each diagnostic subtype, survival was estimated using the Kaplan-Meier model and the log-rank test was used to test of differences in survival curves according to diagnostic subtype. Hazard ratios (HRs) were also adjusted for age and sex using Cox regression.

The analyses were performed using SAS software (version 9.4).

Results

Study population

Data from 26,525 demented patients followed in the network and fulfilling inclusion criteria were extracted. Among them, 2,369 have first been seen at the MRRC (Lille tertiary-referral MC), and 24,156 first at one of the MCs belonging to the network.

During the 7 years of follow-up, 690 incident cases of FTD syndromes were identified, giving a crude incidence rate of 2.42 per 100,000 person-years (Table 1). The FTD incidence across age groups at diagnosis reached its peak in the 75-to-79 year-old group, with an incidence rate of 14.95 per 100,000 person-years. The age-standardized incidence rate was 2.90 per 100,000 person-years.

FTD syndromes represented 2.6% of the studied population, as compared with 71% AD (Figure 1A).

Among FTD syndromes 64% were bvFTD, 17% lvFTD and 18% mFTD (Table 2). The proportion of FTD syndromes was higher in the MRRC (8.1%) than elsewhere (2.0%).

Characteristics of patients with FTD syndromes

The sex ratio significantly differed between AD and FTD patients (p<0.0001, d=0.1) (Table 2). Men represented 47% of FTD and only 30% of AD patients. Patients with FTD syndromes were younger than those with AD at first referral (70.4 vs. 80.6 years, p<0.0001), and bvFTD patients were younger than the remaining FTD syndromes (69.4 vs. 72.3 years). MMSE scores at first referral were higher in FTD syndromes than in AD (21.8 vs. 18.9, p<0.0001, d=0.5).

Likewise, the median IADL-4 score was higher in patients with FTD syndromes compared to AD patients (3 vs 2, p<0.0001, d=0.5), favoring a more preserved autonomy in instrumental activities.

Among the FTD syndromes, a positive family history of dementia was identified in 14%, as compared with 2.3% of AD patients (p<0.0001, d=0.1). Among the 294 FTD syndromes referred to the MRRC, a genetic mutation was detected in 34% of the 99 patients in whom the genetic analysis was performed (47% in C9Orf72, 32% in PGRN and 21% in MAPT genes). Mutations were more likely to be retrieved in bvFTD (95%) than in lvFTD (5%) or mFTD (0%). See Table 1 for detailed comparisons between FTD syndromes and AD.

Diagnosis of FTD syndromes

We then systematically studied the time to referral, time to diagnosis and diagnostic workup of FTD compared to AD patients. Referral delay was longer for FTD syndromes compared to AD (37.6 vs. 31.8 months, p<0.0001, d=0.4). Among the FTD syndromes, referral delay was the highest for bvFTD (40.0 vs. 33.3 months in other FTD). Diagnosis wandering was longer for FTD syndromes compared to AD (9.8 vs. 5.8 months, p<0.001, d=0.1), but similar across FTD syndromes.

As part of the standardized dementia diagnosis procedure, all of our patients performed an MRI, if not contraindicated. The diagnostic workup of FTD patients in the whole Méotis network included more often a FDG-PET and a lumbar puncture that the one of AD patients (23.2% vs 2.6% and 27.5% vs 3.96% respectively, p<0.001 and d=0.2 for both comparisons, Table 2). Brain imaging and lumbar puncture were more consistently used in Lille MMRC both for AD and FTD diagnosis (our unshown data).

Correlations between clinical diagnoses and pathology were excellent in the 15 patients of the study population who came to autopsy. Among the patients with available pathological examination, the 4 in the bvFTD group had FTLD-TDP (n=3) or FTLD-FUS (n=1) pathologies. All 5 patients in the mFTD group had PSP or CBD pathology. All 6 patients in the AD group had AD pathology +/-cerebral amyloid angiopathy or Lewy body pathology (n=3 and 2, respectively).

Natural history of FTD syndromes

Cognitive progression estimated by the rate of MMSE decline was then assessed. Overall, there was no significant difference in the rate of MMSE decline between FTD syndromes and AD. Across FTD syndromes, bvFTD did not significantly differ from AD in the rate of MMSE decline per year (the slope was abvFTD=-2.0 in bvFTD against aAD=-1.8 in AD, p=0.4). However, the decline was higher in lvFTD (alvFTD=-2.8) and mFTD (amFTD=-2.6) than in AD patients (p=0.003 and p=0.02, respectively) (Figure 1B). Follow-up was longer for FTD syndromes compared to AD (24.1 vs. 17.5 months, p<0.0001, d=0.2) and more specifically, bvFTD and lvFTD patients had a significantly longer follow up than AD patients.

As of September 2020, 48% of bvFTD, 53% of lvFTD, 76% of mFTD and 59.1% of AD patients had died (Table 2). The median survival time after diagnostic was 5.5 years for the entire sample and varied significantly according to the diagnosis subtype (6.5 years for bvFTD, 6.1 for lvFTD, 5.5 for AD and 4.0 for mFTD, p<0.001) (Figure 1C). Age (HR [CI 95%] = 1.05 [1.05-1.06] for one year, p<0.001) and male sex (1.73 [1.67-1.80], p<0.001) were significantly associated with an increased risk of death. After adjustment for age and sex, mFTD were significantly associated with a lower median survival as compared to AD (2.32 [1.89-2.84], p<0.001). There were no significant differences between AD and bvFTD (1.10 [0.96-1.26], p=0.179) and between AD and lvFTD (1.21 [0.94-1.55], p=0.137).

Treatment of FTD syndromes

There were sharp differences in the therapeutic approach between FTD syndromes and AD. FTD patients received less anticholinesterase inhibitors (AChEI) and memantine than AD patients (12.0% vs 42.2%, p<0.0001, d=0.1 and 5.7% vs 21.8%, p<0.0001, d=0.1, respectively). Conversely, FTD patients received more antidepressants (48.0% vs 27.0%, p<0.0001), anxiolytics (33.2% vs 23.6%, p<0.0001, d=0.04) and antipsychotics (17.5% vs 13.1%, p=0.003, d=0.1) than AD patients. The difference between AD and FTD stemmed mostly from the bvFTD group where antidepressants (55.2%), anxiolytics (38.3%) and antipsychotics (24.4%) were used the most (p<0.0001 and d=0.1 for the three comparison to AD). There was no significant difference in the use of hypnotics between groups (Figure 2).

Discussion

The main findings of the present study are threefold: (1) despite new sets of criteria, diagnoses of FTD syndromes remained low in routine care in our regional memory clinic network; when diagnosed, bvFTD patients had longer referral delay and diagnostic wandering than AD patients; (2) the peak of incidence of bvFTD occurred between 75 and 79 years, clearly advocating against the conception of FTD as exclusively an early-onset dementia; (3) FTD syndromes differed from AD with regard to cognition and autonomy at baseline, cognitive decline and disease duration; (4) therapeutic strategies radically differed from the ones in AD.

Misconceptions about FTD lead to underdiagnosis

In this retrospective study, we calculated an FTD age-standardized incidence rate of 2.9/100.000 py in our region. Our results stand in-between the ones of two recent studies using updated FTD criteria that found an incidence of 1.6/100.000 py in the United Kingdom (Norfolk and Cambridgeshire counties) and 3.05/100.000 py in Italy (Leccia and Brescia provinces) [START_REF] Coyle-Gilchrist | Prevalence, characteristics, and survival of frontotemporal lobar degeneration syndromes[END_REF][START_REF] Logroscino | Incidence of frontotemporal lobar degeneration in Italy: The Salento-Brescia Registry study[END_REF]. However, while we used the same European reference population as our British colleagues, Logroscino et al. used the Italian population for standardization. Standardization of their incidence rate with the same European population yields an FTD age-standardized incidence rate of 2.78/100.000 py, strikingly similar to ours (our unshown data).

We found that FTD syndromes represented 3% of the Méotis network caseload. Similar MC surveys in Netherlands [START_REF] Van Der Flier | Amsterdam Dementia Cohort: Performing Research to Optimize Care[END_REF] and Sweden [START_REF] Religa | the Swedish Dementia Registry -a tool for improving the quality of diagnostics, treatment and care of dementia patients in clinical practice[END_REF] had 7% and 3.6% of FTD syndromes, respectively. However, all patients in the Dutch cohort were followed in the Alzheimer centre of the VU University Medical Center (VUmc), a tertiary centre where atypical dementias are likely to be addressed, possibly leading to an overrepresentation of FTD patients. Likewise, there was a 8.1% proportion of FTD patients in Lille tertiary centre. A recent review on the epidemiology of FTD highlighted three studies with high methodological standards [START_REF] Hogan | The Prevalence and Incidence of Frontotemporal Dementia: a Systematic Review[END_REF]. In these publications using the Lund and Manchester [START_REF]Clinical and neuropathological criteria for frontotemporal dementia. The Lund and Manchester Groups[END_REF] or Neary [START_REF] Neary | Frontotemporal lobar degeneration[END_REF] criteria, FTD syndromes accounted for 1,1% [START_REF] Gurvit | The prevalence of dementia in an urban Turkish population[END_REF], 3% [START_REF] Gascón-Bayarri | Prevalence of Dementia Subtypes in El Prat de Llobregat, Catalonia, Spain: The PRATICON Study[END_REF] and 3.8% [START_REF] Andreasen | Prevalence and Incidence of Clinically Diagnosed Memory Impairments in a Geographically Defined General Population in Sweden[END_REF] of dementia cases, which is consistent with our findings.

In sharp contrast, consistent with the underdiagnosis of FTD, systematic neuropathology surveys show much higher figures. In UK brain banks from donors (of whom two thirds had dementia), FTD represented 5.1% of diagnoses [START_REF] Francis | Brains for Dementia Research: Evolution in a Longitudinal Brain Donation Cohort to Maximize Current and Future Value[END_REF] and up to 9.4% of elderly people participating in a community brain donation program were found to have some FTD lesions at autopsy [START_REF] Beach | Arizona Study of Aging and Neurodegenerative Disorders and Brain and Body Donation Program[END_REF].

The reasons for FTD underdiagnosis are manifold. First, late-onset FTD are often overlooked. FTD is historically considered as a major cause of early onset dementia [START_REF] Ratnavalli | The prevalence of frontotemporal dementia[END_REF], which probably contributes to FTD diagnosis being overlooked in late-onset dementia. Yet, in recent studies with pathological confirmation, one fourth of FTD cases had an age at onset >65 years [START_REF] Seo | Early vs late age at onset frontotemporal dementia and frontotemporal lobar degeneration[END_REF]. In the recent literature, there is a trend toward an increase in the age at diagnosis of FTD syndromes, which may relate to the increasing age at dementia diagnosis in recent surveys [START_REF] Chen | Twenty-year trends in patient referrals throughout the creation and development of a regional memory clinic network[END_REF]. While older studies showed an age at diagnosis of 65.9 years [START_REF] Borroni | Is early-onset clinically different from lateonset frontotemporal dementia?[END_REF], we found an age at diagnosis of 71.3 years, which compares to recent publications showing a mean age at diagnosis of 69.4 [START_REF] Nilsson | Age-related incidence and family history in frontotemporal dementia: data from the Swedish Dementia Registry[END_REF], 70.0 [START_REF] Turcano | Incidence of frontotemporal disorders in Olmsted County: A population-based study[END_REF] or 71.3 years [START_REF] Logroscino | Incidence of frontotemporal lobar degeneration in Italy: The Salento-Brescia Registry study[END_REF]. Interestingly, the peak of incidence occurred between 75 and 79 years in our survey as in the aforementioned Italian and English studies [START_REF] Coyle-Gilchrist | Prevalence, characteristics, and survival of frontotemporal lobar degeneration syndromes[END_REF][START_REF] Logroscino | Incidence of frontotemporal lobar degeneration in Italy: The Salento-Brescia Registry study[END_REF], reminding that FTD is not only a dementia of early onset.

Second, the positive diagnosis of bvFTD and its differentiation with primary psychiatric disorders is another diagnostic challenge [START_REF] Ducharme | Recommendations to distinguish behavioural variant frontotemporal dementia from psychiatric disorders[END_REF] that is reflected by the increased time to presentation and time to diagnosis of the bvFTD variants as compared with the others [START_REF] Pasquier | Natural history of frontotemporal dementia: comparison with Alzheimer's disease. Dementia and geriatric cognitive disorders[END_REF][START_REF] Woolley | The diagnostic challenge of psychiatric symptoms in neurodegenerative disease: rates of and risk factors for prior psychiatric diagnosis in patients with early neurodegenerative disease[END_REF]. Prolonged diagnostic wandering in bvFTD, associated in our study with an increased reliance on diagnostic biomarkers, seems to be a universal finding [START_REF] Van De Vliet | Time to diagnosis in young-onset dementia as compared with lateonset dementia[END_REF][START_REF] Zhao | Delayed help seeking behavior in dementia care: preliminary findings from the Clinical Pathway for Alzheimer's Disease in China (CPAD) study[END_REF][START_REF] Coyle-Gilchrist | Prevalence, characteristics, and survival of frontotemporal lobar degeneration syndromes[END_REF] and suggests that many cases could remain misdiagnosed. Future studies should focus on the exact determinants of the delay in referral and in diagnosis. Third, all the possible clinical presentations of FTD have not been thoroughly described and some are not taken into account by the available clinical criteria. The amnestic variant of FTD, in particular, is difficult to differentiate from AD [START_REF] Bertoux | Two distinct amnesic profiles in behavioral variant frontotemporal dementia[END_REF][START_REF] Nelson | Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report[END_REF] in particular in late-onset dementia [START_REF] Bertoux | Does amnesia specifically predict Alzheimer's pathology? A neuropathological study[END_REF]. Another example is the right temporal variant of FTD although a recent publication proposing clinical criteria will contribute to fill the gap [START_REF] Ulugut Erkoyun | A clinical-radiological framework of the right temporal variant of frontotemporal dementia[END_REF].

Overall, our survey confirms that FTD are still probably overlooked despite the use of novel clinical criteria and incorporation of new phenotypes. While progress has been made in the recognition of lateonset forms, differential diagnosis between FTD and AD remains a challenge, particularly in the oldest old, and bvFTD cases are probably still mistaken for primary psychiatric disorders.

FTD syndromes differ with AD in baseline characteristics and natural history

We found several key differences between FTD syndromes and AD at baseline. First, as we had previously shown [START_REF] Pasquier | Natural history of frontotemporal dementia: comparison with Alzheimer's disease. Dementia and geriatric cognitive disorders[END_REF], we confirmed that the MMSE score is higher in FTD. However, behaviour, social cognition and executive functions, the main domain impaired in bvFTD, are not properly assessed by the MMSE, which somewhat undermines the assumption that the general cognitive status is better preserved in FTD syndromes. The higher IADL-4 score in FTD compared to AD contrasted with past studies that retrieved either lower [START_REF] Mioshi | Rate of change of functional abilities in frontotemporal dementia[END_REF] or equal [START_REF] Larner | Re: Activities of daily living in frontotemporal dementia and Alzheimer disease[END_REF] autonomy. However, IADL-4 only assesses restriction in four activities (telephone, transportation, drug treatment, and finances) that are best associated with future dementia risk [START_REF] Pérès | Natural history of decline in instrumental activities of daily living performance over the 10 years preceding the clinical diagnosis of dementia: a prospective population-based study[END_REF], thus preventing a direct comparison of our results with studies that employed the full ADL. The younger age and the better preservation of memory and visuo-motor functions, may explain the lesser impairment found in FTD as compared to AD. Impaired functional capacity in bvFTD is primarily due to behavioral symptoms and impaired social cognition, and the routine (although complex) instrumental activities of the IADL-4 may not be the most representative of the loss of autonomy in FTD syndromes. Among the FTD syndromes, the lvFTD patients had the most preserved autonomy, as found in previous studies [START_REF] Mioshi | Rate of change of functional abilities in frontotemporal dementia[END_REF][START_REF] Larner | Re: Activities of daily living in frontotemporal dementia and Alzheimer disease[END_REF].

Although FTD syndromes as a whole had a similar rate of MMSE decline to AD, lvFTD and mFTD variants specifically showed a higher rate of MMSE decline in time. Additionally, lvFTD had a slightly lower score at baseline than the other variants. Since the MMSE relies mostly on language, aphasia have likely impacted the score in lvFTD. In recent studies, patterns of longitudinal MMSE decline across the FTD phenotypes have already been studied, and semantic dementia cases were shown to decline the most [START_REF] Tan | Differential longitudinal decline on the Mini-Mental State Examination in frontotemporal lobar degeneration and Alzheimer disease. Alzheimer disease and associated disorders[END_REF]. Regarding survival, we, as others [START_REF] Coyle-Gilchrist | Prevalence, characteristics, and survival of frontotemporal lobar degeneration syndromes[END_REF], reported that mFTD had the more severe prognosis of FTD syndromes [START_REF] Coyle-Gilchrist | Prevalence, characteristics, and survival of frontotemporal lobar degeneration syndromes[END_REF], followed by lvFTD and bvFTD. Despite similar MMSE decline rates between bvFTD and AD, mFTD patients had a significantly lower survival median.

Therapeutic strategies in FTD

The drug treatments used in FTD syndromes markedly differed from the ones used in AD. These observations should be interpreted with caution since differences may only reflect different customs, and not different responses to treatment. However, clinical guidance on the symptomatic treatment of FTD is limited [START_REF] Trieu | Effectiveness of Pharmacological Interventions for Symptoms of Behavioral Variant Frontotemporal Dementia: A Systematic Review[END_REF], prompting physicians to use psychotropic drugs that may be used non-specifically in dementia, based on the medical needs and immediate efficacy. Hence the prescription habits in FTD may also reflect the neuropsychiatric symptoms and treatment response of FTD patients.

A publication from the Boxer's group showed that off-label use of AChEI and memantine in FTD was common in the US in 2010 [START_REF] Hu | Off-label medication use in frontotemporal dementia[END_REF]. In our region and in the 2010-2019 time span, we found that AChEI and memantine were used in only 12.0% and 5.7% of FTD syndromes, in accordance with recent data supporting lack of efficacyor even deleterious effects in bvFTD and mFTD ( [START_REF] Mendez | Preliminary Findings: Behavioral Worsening on Donepezil in Patients With Frontotemporal Dementia[END_REF][START_REF] Vercelletto | Memantine in behavioral variant frontotemporal dementia: negative results[END_REF], reviewed in [START_REF] Tsai | Treatment of Frontotemporal Dementia[END_REF][START_REF] Tsai | Therapy and clinical trials in frontotemporal dementia: past, present, and future[END_REF]). The remaining prescriptions may reflect diagnostic hesitations with AD at the beginning of follow-up.

Antipsychotics and anxiolytics were more frequently used in FTD syndromes than in AD, and the difference with AD was driven by the bvFTD variant. Antipsychotics are prescribed to treat agitation in dementia whatever the aetiology (AD, FTD or others) [START_REF] Ringman | Treatment Options for Agitation in Dementia[END_REF], although their use is restricted to patients with severe symptoms (aggression, agitation, or psychosis) who fail to respond adequately to other pharmacological and nonpharmacological treatments. The use of anxiolytics and antipsychotics in 38.3% and 24.4% of bvFTD patients, as opposed to 23.6% and 9.3% in AD, is thus a reflexion of the higher rate of productive behavioural symptoms (e.g. agitation, aggression, and psychosis) in this variant. However, the low rate of antipsychotics use in FTD demonstrated that physicians took into account the alerts on side effects [START_REF] Kerssens | Vulnerability to neuroleptic side effects in frontotemporal dementia[END_REF][START_REF] Pijnenburg | Vulnerability to neuroleptic side effects in frontotemporal lobar degeneration[END_REF] and increased mortality rate [START_REF] Gill | Syncope and its consequences in patients with dementia receiving cholinesterase inhibitors: a populationbased cohort study[END_REF] in FTD and dementia patients treated with antipsychotics. The black box warning from the Food and Drug Administration was followed by a similar warning from the French Haute Autorité de Santé in 2009 (https://www.hassante.fr/jcms/c_885227/fr/limiter-la-prescription-de-neuroleptiques-dans-la-maladie-d-alzheimer) that had found a strong echo in the neurologic and geriatric communities.

The most remarkable difference however regarded the prescription of antidepressants, which was twice as important in bvFTD (55.2%) as in AD (27.0%). Indeed, although results are mixed, comprehensive reviews of the evidence from clinical trials favoured the use of selective serotonin reuptake inhibitors to treat behavioural symptoms [START_REF] Trieu | Effectiveness of Pharmacological Interventions for Symptoms of Behavioral Variant Frontotemporal Dementia: A Systematic Review[END_REF][START_REF] Tsai | Treatment of Frontotemporal Dementia[END_REF][START_REF] Tsai | Therapy and clinical trials in frontotemporal dementia: past, present, and future[END_REF][START_REF] Huey | A systematic review of neurotransmitter deficits and treatments in frontotemporal dementia[END_REF]. Our team in particular demonstrated that trazodone, a serotonin antagonist and reuptake inhibitor, reduced irritability, agitation, and depressive symptoms in FTD [START_REF] Lebert | Frontotemporal dementia: a randomised, controlled trial with trazodone[END_REF]. The much better tolerance profile and apparent efficacy of serotonin-acting drugs logically imposed them as the mainstay of FTD treatment in our network.

Strengths and limitations

This naturalistic study of a 6-year period is rooted in 23 years of data sharing and harmonization across a regionwide memory clinic network [START_REF] Chen | Twenty-year trends in patient referrals throughout the creation and development of a regional memory clinic network[END_REF]. It allowed to analyse the trends of real-life FTD diagnosis and care over time. We reached a considerable number of new patients per year, equivalent to the one of nation-wide MC networks. Analyzing the characteristics of consecutive FTD patients first referred between 2010 and 2016 allowed us to focus on patients in which the diagnosis was made using the new criteria for bvFTD and lvFTD [START_REF] Rascovsky | Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia[END_REF] and strengthened by follow-up. By considering a wide spectrum of FTD variants, we included patients that are often withdrawn from FTD cohorts.

Our survey confirmed many previously published data, which reinforces of the quality and validity of our database. We showed that approximately two thirds of FTD patients had a behavioural variant (bvFTD), and 17% had a language variant, which matches other databases [START_REF] Hogan | The Prevalence and Incidence of Frontotemporal Dementia: a Systematic Review[END_REF][START_REF] Johnson | Frontotemporal Lobar Degeneration: Demographic Characteristics of 353 Patients[END_REF][START_REF] Ioannidis | The frontotemporal dementias in a tertiary referral center: classification and demographic characteristics in a series of 232 cases[END_REF]. We, as others, found a sex ratio of approximately 1:1 in FTD [START_REF] Hogan | The Prevalence and Incidence of Frontotemporal Dementia: a Systematic Review[END_REF]. Thirty-five percent of our FTD patients had a family history of neuropsychiatric disease, in agreement with the literature [START_REF] Rosso | Frontotemporal dementia in The Netherlands: patient characteristics and prevalence estimates from a population-based study[END_REF][START_REF] Goldman | Comparison of family histories in FTLD subtypes and related tauopathies[END_REF]. Only our rate of mutations was lower than previously reported since a mutation was identified in C9ORF72, MATP or GRN in only 6% of the FTD patients that had a genetic analysis, against 10-15% in the literature [START_REF] Sellami | Genetic forms of frontotemporal lobar degeneration: Current diagnostic approach and new directions in therapeutic strategies[END_REF]. Last but not least, pathological diagnoses when available matched the clinical diagnoses, confirming the high accuracy of the clinical diagnoses made in a structured regional network and confirmed by a prolonged follow-up.

Our survey has however a few limitations. First, important data are not systematically populated in our database. We still lack accurate cognitive, functional or disease-specific scales to assess disease progression. Furthermore, the mean follow-up of ~2 years precludes a comprehensive overview of FTD progression in many of our patients. We also acknowledge a selection bias due to the different networks involved in movement disorders and dementia care in our region, an issue that had been acknowledged in similar studies. Patients with overt motor neuron disease at presentation were not included because they were referred to a specialized regional care pathway rather than to memory clinics. Likewise, the PSP and CBS patients that were referred to our memory clinics were probably the ones presenting early behavioural and/or cognitive changes. Conversely, PSP and CBS with prominent motor symptoms were likely to be followed in movement disorders clinics, where secondary referral to MCs is not systematic.

Still, our incidence rate compares to the ones of two regional cohorts including the full FTD spectrum [START_REF] Coyle-Gilchrist | Prevalence, characteristics, and survival of frontotemporal lobar degeneration syndromes[END_REF][START_REF] Logroscino | Incidence of frontotemporal lobar degeneration in Italy: The Salento-Brescia Registry study[END_REF].

Conclusion and outlook

Overall, our study showed that FTD syndromes have specific clinical features, different progression patterns and therapeutic strategies. Yet, even in a region with an organized memory clinic network, FTD is still overlooked and diagnosis wandering remains longer than in AD. Psychiatric, amnestic and/or lateonset presentations of FTD are particularly treacherous, and the overlap between cognitive/behavioral and motor presentations leads to an underestimation of the motoric presentations of FTD in memory clinics.

There is an obvious need of accurate FTD biomarkers to improve FTD diagnosis. Until and even after the avenue of such biomarkers, neuropsychology has and will have a role to play at a limited cost. The development of novel tests exploring new domains of social cognition beyond mentalization and emotion recognition is a steppingstone in this direction. Social cognition deficits have been found to be a reliable and effective cognitive marker of FTD, especially in patients with a psychiatric [START_REF] Bertoux | Social Cognition and Emotional Assessment differentiates frontotemporal dementia from depression[END_REF] or amnestic [START_REF] Bertoux | Sensitivity and specificity of ventromedial prefrontal cortex tests in behavioral variant frontotemporal dementia[END_REF][START_REF] Bertoux | So Close Yet So Far: Executive Contribution to Memory Processing in Behavioral Variant Frontotemporal Dementia[END_REF] presentations. Social cognition deficits are probably underestimated in mFTD as well [START_REF] Ghosh | Social cognitive deficits and their neural correlates in progressive supranuclear palsy[END_REF], advocating for a more systematic assessment of social cognition in memory, geriatric, movement disorders and psychiatry clinics. In order to improve FTD diagnosis, the classical boundaries between specialties should be broken. Indeed, it is only through a harmonization in diagnostic procedures and databases involving geriatricians, movement disorders specialists, old-age psychiatrists, neuropsychologists, speech-therapists and memory clinics that the real scope of FTD will be thoroughly apprehended. The gathering of these different disciplines into consortiums such as the Centers of Excellence in Neurodegeration (CoEN) responds to this objective.

Additionally, initiatives are needed to raise awareness on FTD in the general population. At the eve of disease-modifying therapies, misdiagnosis of FTD may already be a loss of opportunity for patients.

Tables and figures

Figure 1 .

 1 Figure 1. Characteristics and progression of patients with FTD syndromes in the Méotis network (incident cases from 2010 to 2016). A. Aetiologies of dementia in the incident cases. B. Mixed linear model of the evolution of the MMSE over time in patients with FTD syndromes and AD. C. Survival in patients with FTD syndromes and AD

Figure 2 .

 2 Figure 2. Drug treatments used in FTD syndromes compared to AD

Table 1 . FTD incidence rates, number of cases, and number of person-years by age group

 1

	Age group	Number of	Number of	Incidence (per 100,000
	at diagnosis	cases	person-years	person-years)
	0-39	2	14,854,742	0.01
	40-44	3	1,922,550	0.16
	45-49	8	1,842,470	0.43
	50-54	25	1,862,287	1.34
	55-59	61	1,796,207	3.40
	60-64	95	1,703,044	5.58
	65-69	123	1,490,146	8.25
	70-74	110	828,709	13.27
	75-79	126	842,548	14.95
	80-84	92	725,613	12.68
	≥85	45	676,866	6.65
	Total	690	28,545,202	2.42

Table 2 . Demographics and clinical features of FTD syndromes

 2

		bvFTD				lvFTD			mFTD		AD
		N= 446			N= 118			N = 126		N = 18831
	Variable	Value	NA	p*	Value	NA	p*	Value	NA	p*	Value	NA
	Women, n (%)	232 (52.2)	0	<0.001	68 (57.6)	57.6	0,01	68 (54)	0	< 0,001	13162 (69.9)	0
	Age at first visit, m (sd)	69.4 (10.3)	0	<0.001	72.7 (9.5)	0	<0.001	72.0 (8.0)	0	<0.001	80.6 (7.5)	0
	Age at diagnosis, m (sd)	70.2 (10.3)	0	<0.001 73.6 (9.7)	0	<0.001	72.8 (8.1)	0	<0.001	81.0 (7.3)	0
	Delay referral (months), m (sd)	40.0 (41.2)	87	<0.001	30.8 (20.5)	19	0.84	35.8 (29.9)	24	0.13	31.8 (32.0)	5370
	Diagnosis wandering (months), m (sd)	9.9 (16.8)	0	<0.001	10.5 (16.4)	0	<0.001	9.1 (15.1)	0	<0.001	5.8 (14.2)	0
	Clinical follow up (months), m (sd)	25.2 (24.0)	0	<0.001	24.2 (22.0)	0	<0.001	20.2 (19.6)	0	0,05	17.5 (21.4)	0
	Dementia family history, n (%)	75 (16.8)	0	<0.001	11 (9.3)	0	<0.001	13 (10.3)	0	<0.001	508 (2.7)	0
	MMSE at first visit, m (sd)	22.1 (6.1)	117	0,02	20.6 (7.5)	27	0.002	21.9 (6.1)	38	<0.001	18.9 (6.0)	2246
	IADL-4, median	3	199	<0.001	4	38	<0.001	3	54	< 0.001	2	6689
	PET in the network, n (%)	117 (26.2)	0	<0.001	18 (15.2)	0	<0,001	25 (19.8)	0	<0.001	484 (2.5)	0
	CSF in the network, n (%)	135 (30.3)	0	<0.001	22 (18.6)	0	<0,001	33 (26.2)	0	<0.001	759 (3.9)	0
	Death, n (%)	213 (48.4)	0		63 (53.4)	0		96 (76.

Acknowledgements

The authors thank Catherine Ficot, Nathalie Jourdan and Brigitte Leprince for their continuous energetic contribution to the network as well as the overall Méotis.

The authors also thank Antoine Lamer and the MatchID team for their help in retrieving the dates of death.

Funding

The study was partially funded by laboratory of excellence DistAlz.

Availability of data and materials

The datasets considered in the current study are available from the corresponding author on reasonable request.

Abbreviations

AD: Alzheimer's disease

Declarations

Ethics approval and consent to participate

The database was declared to the ad hoc commission (Commission Nationale Informatique et Libertés (CNIL)) protecting personal data (#2146189V1). Privacy and confidentiality rules were respected.

Consent for publication

Not applicable

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

ML did the study concept and design, the analysis and interpretation of data, drafted the manuscript, revised the manuscript for important intellectual content, statistical analysis, administrative support. MB did the study concept and design, the interpretation of data and revised the manuscript for important intellectual content. ES did the statistical analysis and revised the manuscript for important intellectual content. EM did the analysis and interpretation of data and revised the manuscript for important intellectual content. CAB, SB, PC, YC, VD, FL, MAM, ARS, FP and the Méotis network collected the data and revised the manuscript for important intellectual content. MW did the statistical analysis of the incidence and survival. ILB performed the genetic analysis. TL did the study concept and design, the analysis and interpretation of data, drafted the manuscript, revised the manuscript for important intellectual content and supervised the overall study.

Authors' information (optional)

Not applicable