Karine Pinel

MATERIAL, TEXTURE AND PATTERN CONSTRUCTION IN A CONTEMPORARY ART OF FILTER: FACTUAL AND ACTUAL PLASTIC

Keywords:

Researcher artist, I have been working on relations between making art object and phenomenons characterizing ways of appearing. I have chosen to consider the question of showing art construction multiplicity modes, art production complexity (concrete and visual object at the same time).

This study looks at the artist's point of view and namely his or her artistic choice to make the work visible using the effects of colour expression. How does the artist use colour expression as a material and subject of the work? What is the thinking?

The artist experiments with the raw material, working on it in order to induce visual responses, observing and classifying the expressions of colour in line with what is being done to it. The idea behind this study is to correlate colour phenomena with work done on the raw material.

INTRODUCTION

Is it not through the coming together of raw materials and through developing knowledge of the visual effects produced by his or her work on these raw materials, that the artist can master his or her own creative process? Are raw materials not the work's true materials due to their visuals responses?

If, as Malevitch stated, optical perception is the painter's real material, then colour expression is the raw material of the work. The artist seeks sensitive, technical and experimental knowledge of the raw material in light of its organization and in line with its visual qualities. The artist carries out research in the aesthetic sphere: linking physical properties to properties which can be seen by the eye. He considers "actual plastic" as characterized by Joseph Albers (the visual state): what can be seen in the coming together of the types and qualities of raw materials used (including colorants), the tensions produced in the layout of these raw materials and the quality and direction of the light source. The artist tackles phenomena resulting from this coming together of raw material and light in an empirical and sensitive way. He considers the work based on how it lends itself to being seen in a certain way. But this "actual plastic" is closely linked to the use of the raw material, to the "factual plastic" as characterized by Joseph Albers (artistic reality): what the object actually is.

The study was based on considering the raw material experimentation phase: it was a question of observing and identifying different expressions of colour depending on the type of work done on the raw material or the layouts. The study was based on an uncommon artistic practice in the field of filter art, on my own creation. Familiar with mural art ( as tapestry and stained-glass window), they are made from a composite material of my own : a mix of resin, textile and dynamic colour. Flexible and translucent pieces vertically positioned, they filter the light from the outside to the inside. Fixed or in move, their colours are adjusting themselves in the living space according to the nature of light and the hygrometry level surrounding.

COLOUR EXPRESSION AND PATTERN CONSTRUCTION

2.1 Work done on the raw material and visual responses.

A practice

My experience of working with raw materials led me to produce filters. However, I had to carry out numerous experiments, comparisons, measurements and work before being able to set out real pattern construction. Indeed, it was only by developing my knowledge of the materials that I was able to master the effects produced by their interaction. It was the raw materials themselves, which, becoming the filter's components, provided me with visual responses. The creation of a composite fabric is the result of sensitive, technical and experimental knowledge of the materials in use, as well as the definition of the visual constraints.

By way of a frontal, flexible substrat (substrate), a fine transparent fabric with wide mesh was used. The colorant, metal salt, was chosen for its physical properties: it has a light shine and a light coating capacity. It therefore frees the artist up to work on transparency.

The binder which enabled the composite fabric to be created, the links between the textile fibres and the colorant, is a plastic resin. It is produced using polycondensation. The binder was chosen due its specific state at the "finished product" stage: transparent and elastic thus enabling the colorant to express the colours.

Experiments and visual events

My experiments focused on bringing different resins into contact with the substrate in order to analyse the visual responses obtained.

The resins received the colorant in two ways: either through mixing (resin and colour blended together manually) or through inclusion (the colour is spread on the surface, absorbed and then immobilised in an uneven way by the resin.) During the work the colorant particles were coated by the resin and then set when polycondensation took place. Some factors led to irregular distribution of the coloured particles. This was the case for the technique of spreading in the resin: localised or wider sprinkling of grains of different sizes, or dilution in the resin itself, caused these coloured particles to be spread out in stains, in a scattered fashion or in very highly concentrated areas (see figure 1), namely in groups of particles of varying densities of indeterminate shapes and which visually produce vibrations (shining.)

Figure 1 My actions during the reticulation process, which were carried out with the aim of shaking it up, also contributed to producing the current colours. They may appear as air bubbles, cuts, crawling or folds in the resin.

Pigment concentration gradations, visual irregularities and therefore variations in the transparency, tones, colour intensity and shine all result from the spread of the colorant in the suspension space (namely its even or uneven distribution in the binder) as well as the type of volume drying.

The pattern construction resulting from these experiments will constitute the hazy colour effect, which will make the colour dynamic visually palpable. The real nature ("factual plastic") of the raw material gives off a coloured vibration. But how can this mess of particles be organized?

Interior design and « actual » colours.

Pattern construction

As a tribute to clouds, which are by definition natural filters, I proceeded to bring the troposphere cloud mass distribution model into the heart of my work. If the scientific model of this distribution enables unstable atmospheric phenomena to be rationalized, in the same way the reuse of this model within the pictorial sphere rationalizes the spatial distribution of different pictorial stratum and therefore the distribution of the work's materials. Therefore, "interior design" must be understood to be the sketching of the work's visual space in line with a visual structuring requirement.

Factual plastic distribution

I have called the linking of the raw materials in a distribution over the substrate a strate nébuleuse (nebulous stratum), on the understanding that this stratum can be superimposed over one another and can contribute to the depth of the pictorial volume in accordance with different artistic choices (for example selecting a specific form of opacity for the work). The strate nébuleuse is made up of the combination of the colorant with the resin, with the resin being the suspension space. The nature of the drying equipment used for the strate nébuleuse (film, plastic sheet etc.) modifies the state of the stratum's surface (prints caused by the resin.) I called the frontal distribution of the colorant in the suspension space the domaine nébuleux (nebulous domain). It enters into the geographical area occupied in the plan (vertically and horizontally) by superimposing of the strate nébuleuse.

Therefore colour is a "factual motif" (real motif). Both reticular and territorial, it is geographically modulated and ordered in three dimensions: colour masses enter the areas of the pictorial space in a juxtaposition of coloured stains (domaine nébuleux) and superimposing the coloured stains (strate nébuleuse.) In other words colour is the motif in the spatial juxtaposition of domaines nébuleux which are interlinked in a spatial stratification.

Actual colours

Three actual colours types have been distinguished and analysed depending on the work carried out and how they "update", which means their ability to change over time in line with variable conditions (natural or artificial light, drop or increase in luminosity.) These colours are produced by light passing through artistic reality.

The first is generated by the radiance principle as characterized by Viollet Le Duc (the principle has since been updated by Jean-Claude Merlin's research work.) Radiance changes depending on the quality of light, the type of colour suspension material, as well as the physical arrangement of colour molecules in the suspension space. But it also adjusts according to a certain strength which is linked to a principle, namely that of optical density. If we consider the radiance phenomenon as a colour production by transparent bodies parameter, optical density is the link between the nature of the light crossing the transparent material (L), the thickness of the transparent material (T), the concentration of coloured particle molecules in suspension (C), the nature of the particle upon which hinges the absorption (A) and the quantity of beams transmitted (BT). If T, C or A are raised, BT is weak. In that case we can talk about a high optical density. If T, C or A are weak, BT is strong. In that case we can talk about a low optical density. Furthermore, L must be taken into account because it too modifies the parameters, as light can be natural but filtered (clouds and trees etc.) or artificial and, in this scenario, can have different colour temperatures (visible light.) Surfaces do not only show light due to colour, but depths also select light due to it.

The transparent raw material simultaneously reveals the colour that it rejects and the colour that it traps. The strength of radiance therefore adapts depending on the combination between the quality of light and its direction, the depth and irregularities which are on the colour suspension material, the topographical layout of the colour particles in the material and the chemical and mechanical characteristics of these particles. The result of the light's journey through the pictorial space is the creation of a colour intensity which is even more marked than the pictorial space, as a whole, and is also made up of surface irregularities. In figure 2 we give examples of different radiances linked to different intensities of light.

Figure 2 The second colour is generated by the major principle defined by Goethe.

In his "Theory of Colours", Goethe analysed the phenomenon of colour production when light crosses a transparent or translucent body (gaseous, liquid or solid) but unlike Viollet Le Duc, Goethe only dealt with colourless bodies: direct sunlight seen through different degrees of blurring (from perfect transparency, to the first degree of blurring, up to white, total blurring, and the first degree of opacity) becomes increasingly redder due to the increase in opacity. Indirectly observed light becomes pale blue through dense blurring. He called this colour production a primordial phenomenon. Due to the fact that the nebulous system is a translucent space which is made up of angles which filter the light (whether or not there are colour particles present), this constrains the light to appear in line with this phenomenon. Figure 3 The last of the colours is projected. It is a secondary image (or cast shadow.) It results from a modulation of the light caused by the pictorial space playing the role of a filter. It appears outside the object on the neighbouring space depending on the strength of the radiance from the encounter between light and filter, on the proximity of the filter to that neighbouring space and in line with the absorptive and reflective qualities of the materials which make up the space (figure 4.) For a white projection space equipped with a certain sort of surface and for a given strength of radiance, the closer the filter is to that space, the more faithful the projected colour is to the filter colours. In this way, the projected colour can be called a secondary image. The further away the filter is, the less precise the colour is, and in this scenario it becomes a cast shadow. The projected colour is the combination of the light and the shadow emanating from the filter object. The object's visual space can now be constructed using knowledge of the colour's visual space.

CONCLUSION

Within the framework of art, this study provides planning criteria for the creative act: it enables eduction practices to be directed (knowing that Maurice Fréchuret defined the eduction practice as "…an action through which an efficient cause acts on a raw material and causes a determined form to appear.") This study demonstrates that, within the framework of certain artistic practices, the object's visual space can be built using knowledge of the visual space of colours, with colour itself becoming the work's material and subject. This practice is in no way an exception to the common rule. Pierre Soulages worked in this way on the Abbaye de Conques in order to bring its stained glass windows alive. The radiance principle, the primordial phenomenon and the projected colours were the result of his quest: the expression of light through raw materials.

  is a shot of the same pictorial space lit from the left by an indirect light and from the right by a direct light. It is notable that a bluish colour dominates the left-hand indirect light view and that an orangey colour dominates the right-hand direct light transparent view.

Figure 3

 3 Figure 3

Figure 4

 4 Figure 4


Adolphe J Béquet

Antonio R Hidalgo-Muñoz

Christophe Jallais

Stress variations and auditory omissions: a pilot study

Introduction

The use of auditory alerts is widespread in peripheral monitoring activities, where the attentional focus of the operator can be diverted from the monitored system toward a secondary task [START_REF] Hermann | The sonification handbook[END_REF]. In such activities, an attentional cross-modal phenomenon can arise, leading to omit critical auditory alerts when the operator presents an over-engagement toward a visual task [START_REF] Dehais | Momentary lapse of control: A cognitive continuum approach to understanding and mitigating perseveration in human error[END_REF].

The phenomenon of auditory omissions has been widely studied in aeronautics under the term "inattentional deafness" (ID) [START_REF] Giraudet | Caractérisation de la surdité inattentionnelle, application à la sécurité aérienne[END_REF]. In this context, studies evidenced the existence of an attentional bottleneck impacting both early and late processing of auditory stimulations [START_REF] Durantin | Neural signature of inattentional deafness[END_REF]. These studies were mostly conducted using MEG, EEG and fMRI to explore its neuronal correlates [START_REF] Dehais | A neuroergonomics approach to mental workload, engagement and human performance[END_REF], and secondary tasks employed to induce ID (e.g., during a landing task) were usually specific to the flying context.

Stress is the reaction of an individual towards environmental pressure, on three dimensions including neurophysiological, behavioral, and subjective modulations. Its effects can induce ID through a deleterious impact on regions supporting attentional abilities and executive functions [START_REF] Dehais | Momentary lapse of control: A cognitive continuum approach to understanding and mitigating perseveration in human error[END_REF], or through an attentional bias toward the stressors [START_REF] Eysenck | Anxiety and cognitive performance: Attentional control theory[END_REF]. This pilot study had two objectives:

-Explore the occurrence of ID (behaviorally defined as the occurence of omissions) during a secondary task imitating those which could take place in large-public contexts (e.g., autonomous driving), and its neurophysiological correlates. -Study the suitability of subtle biofeedback stress reduction and examine whether it affects the occurrence of ID [START_REF] Béquet | Toward mindless stress regulation in advanced driver assistance systems: a systematic review[END_REF].

Methods

Twenty-nine participants were included, aged from 19 to 60 years (M=34.1, SD=10.9). The monitoring task consisted of responding "as fast as possible" to auditory alerts by pressing a footswitch. There were 11 alerts, separated by 40 +/-15 seconds in four blocks of 8 min, randomized by an interval of presentation to avoid anticipatory effects and periodical signal contribution (e.g., Mayer waves) in functional Near InfraRed Spectroscopy (fNIRS) acquisition. The secondary task consisted in the memorization and restitution of green light patterns displayed on an 8*8 button touchpad similarly to the "Simon air" game (figure 1). The restitution immediately followed the memorization step. Two levels of difficulty were implemented using pattern length: Easy (from 1 to 7 buttons), and difficult (from 7 buttons, without maximum). Different levels of stress were induced using gauges on both sides of the touchpad: performance evaluation, social and temporal pressure. The biofeedback device emitted slight vibrations throughout the condition, using 2 actuators placed on the inner-wrist [START_REF] Costa | EmotionCheck : Leveraging bodily signals and false feedback to regulate our emotions[END_REF]. Inter-vibration intervals were set to be larger than the actual heartbeat intervals by a factor of 1.5.

Several questionnaires collected subjective feelings (using the Geneva Emotional Wheel and the NASA-TLX) and personality traits (using the Big-Five Inventory). We measured physiological (electrocardiogram, respiration, electrodermal activity) and neurological (using fNIRS) data throughout the experiment.

Results

Behavioral and subjective data

Preliminary results illustrate an impact of stressful blocks on the occurrence of ID (2 nd block: 2 omissions versus 3 rd and 4 th block: 10 and 11, respectively; Χ 2 =5.15, p<.05). Exploratory analysis using Welch's t-test shows that the eight participants experiencing ID are significantly older (M=42.2 years, SD=11.36) than the others (M=31 years, SD=9.21) in the third block (t= -2.49, p<.05, d= -1.14). Furthermore, participants report a higher level of stress felt during the third block (M=2.138, SD=.882 in block 2; M=2.533, SD=.813 in block 3; t=-2.934, p<.005, d= -0.545). There is a moderated impact of the biofeedback on stress level only when extraversion and mental flexibility are included as covariables (M=2.316, SD=.931 in block 4; F=4.933, p<.05, η2=.022).

Neuro-physiological data

Physiological data was processed using Matlab. Extracted parameters were normalized using the first block as baseline. We found an effect of stress on heart rate (M=.007, SD=.069 in block 2; M=.039, SD=.081 in block 3 ; Z=2.650, p<.01, r=-.368), on breathing rate (M=-.007, SD=.061 in block 2; M=.028, SD=.073 in block 3 ; Z=2.242, p<.05, r=-.338), and on the number of electrodermal responses (M=-.276, SD=.384 in block 2; M=-.015, SD=.523 in block 3; t=-2.863, p<.01, d=-.625).

Regarding fNIRS, a processing pipeline adapted from [START_REF] Laurent | Cortical Activity Linked to Clocking in Deaf Adults: fNIRS Insights with Static and Animated Stimuli Presentation[END_REF] was employed. We looked at temporal areas for participants with omissions. There is a significant reduction of oxyhemoglobin concentration change for omissions compared to perceptions (t=-2.238, p<.05, d=-.598). Note that the averaging of omissions signals was conducted on a fewer number of trials than perceptions (21 vs 133).

Conclusions and perspectives

The primary objective was to check whether ID could happen in peripheral monitoring contexts accessible to a large public. While only 3% of alerts were omitted in stressful conditions, results show that older people seem more prone to ID. Preliminary results illustrate that ID can arise within simple tasks and that considering age is relevant. In line with previous works, the occurrence of ID also seems linked to stress, as illustrated by the subjective and physiological results. Moreover, the first fNIRS result regarding participants who failed to notice the alert shows a reduced temporal activation for the omission. This suggests the influence of an attentional bottleneck at an early stage of auditory processing in our experiment. Further analysis on other regions involved in this mechanism and their connectivity to temporal regions will be conducted. Regarding biofeedback, inter-individual characteristics seem to be relevant when studying its efficiency. However, there was no impact on ID nor physiological data.

Additional research investigating the occurrence of ID in a wide-public context would be desirable to ensure the safety of non-expert operators. Specifically, level 3 of autonomous driving presents an interesting application: operators will have perform peripheral monitoring of the vehicle, being authorized to achieve potentially over-engaging secondary tasks (SAE, 2018).

Figure 1 .

 1 Figure 1. Touchpad hardware employed for the secondary task and example of a pattern There were 4 randomized blocks: (1) Control condition with an easy secondary task, (2) Difficult secondary task, (3) Difficult-Stressful secondary task, (4) Difficult-Stressful secondary task and Biofeedback. Each block was 8-minute long and contained both audio and visual tasks.


Spyridon N Karras
email: karraspiros@yahoo.gr.

Panagiotis Anagnostis

Declan Naughton

Cédric Annweiler

Andrea Petroczi

Dimitrios G Goulis

Cedric Annweiler

Vitamin D during pregnancy: Why observational studies suggest deficiency and interventional studies show no improvement in clinical outcomes?

Keywords: hypovitaminosis D, pregnancy, complications, neonate, maternal, supplement

come

Introduction

Pregnancy is a unique state in a woman's life, characterized by a continuum of biologic events that enables tissue maturation, aiming for fetal adaptation to future environmental and nutritional influences [START_REF] Lukaszewski | Nutritional manipulations in the perinatal period program adipose tissue in offspring[END_REF][START_REF] Drever | Fetal programming: Early-life modulations that affect adult outcomes[END_REF]. On this critical time frame, several exogenous stimuli could affect maternal -neonatal syncytium and have an impact on pregnancy outcome, maternal health and future offspring development [START_REF] Lukaszewski | Nutritional manipulations in the perinatal period program adipose tissue in offspring[END_REF][START_REF] Drever | Fetal programming: Early-life modulations that affect adult outcomes[END_REF][START_REF] Poston | Influences of maternal nutritional status on vascular function in the offspring[END_REF]. A wide range of nutritional deficiencies have been recognized as a preventable cause of adverse health events, rendering scientific communities and health organizations worldwide to establish specific nutritional recommendations aiming for optimal fetal development [START_REF] Kulkarni | Nutritional influences over the life course on lean body mass of individuals in developing countries[END_REF]. This suggested diet model, although very similar to a balanced healthy one suggested for most adults, incorporates recommendations, which apply to consumption of micronutrients and vitamins, which have been recognized to be of critical importance in protecting the developing fetus [START_REF] Kulkarni | Nutritional influences over the life course on lean body mass of individuals in developing countries[END_REF][START_REF] Berti | Pregnancy and infants' outcome: nutritional and metabolic implications[END_REF].

On that basis, data from observational studies during the last decade have suggested a potential adverse effect of maternal hypovitaminosis D during pregnancy on maternal and offspring health outcomes [START_REF] Karras | Maternal vitamin D status in pregnancy and offspring bone development: the unmet needs of vitamin D era[END_REF][START_REF] Kovacs | Vitamin D in pregnancy and lactation: maternal, fetal, and neonatal outcomes from human and animal studies[END_REF]. Gradually, interventional studies have been conducted, focusing on the potential beneficial effects of vitamin D supplementation on these outcomes. However, the majority of these studies failed to show any benefit from vitamin D supplementation during pregnancy. The reasons for absence of an agreement between data from observational and supplementation studies remain obscure. The aim of this review was to critically appraise the methodology of the published trials, in an attempt to explain why data from supplementation trials fail to reveal a significant impact on maternal and offspring health outcomes as date from observational studies are suggesting.

Maternal outcomes

Results for pre-eclampsia and gestational diabetes mellitus (GDM) fail to converge to a meaningful outcome, revealing the potential for systematic failures within the field. At that basis, this review included most representative studies on the field according to study sample and methodology (Table 1).

Pre-eclampsia

A series of supplementation studies have examined potential adverse maternal and pregnancy outcomes, mainly pre-eclampsia and GDM. Studies with pre-eclampsia risk reduction as their primary outcome can be divided into observational and randomized. A large, prospective observational trial from Norway (8) studied 23.423 nulliparous women, categorized into two groups, according to the use of vitamin D supplements before or during pregnancy. Vitamin D supplementation during pregnancy with 400 -600 IU daily resulted in 27% risk reduction of pre-eclampsia [odds ratio (OR) 0.73, 95% confidence interval (CI) 0.58 -0.92]. However, the beneficial effect of vitamin D intake should not be attributed to supplementation per se, due to the high intake of vitamin D-rich long n-3 fatty acids in the local diet. In another large, Hungarian study [START_REF] Hyppönen | Vitamin D and pre-eclampsia: original data, systematic review and meta-analysis[END_REF], routine vitamin D supplementation, either as a mono-therapy or contained in a multi-vitamin regimen, with a dose of 3,000 IU/week (average 400 IU/day) starting from the 20 th gestational week, resulted in a reduced risk of pre-eclampsia in a doseresponse manner.

In the field of randomized trials, Marya et al. [START_REF] Marya | Effect of calcium and vitamin D supplementation on toxaemia of pregnancy[END_REF] in a placebo-controlled, non-blinded trial studied two groups of 200 pregnant women (supplementation group: 375 mg calcium and 1200 IU of vitamin D daily from the 20 -24 th gestational week; non-supplementation group: normal diet) and found no statistical difference in the incidence of pre-eclampsia between them. The only blinded, supplementation study available so far [START_REF] Hollis | Vitamin D supplementation during pregnancy: double-blind, randomized clinical trial of safety and effectiveness[END_REF] administered 400 (control group), 2,000 or 4,000 IU of vitamin D 3 daily during pregnancy. Cord blood 25hydroxy-vitamin D [25(OH)D] concentrations were 45.5 ± 25.3 nmol/l in the 2000 IU group and 66.3 ± 25.8 nmol/l in the 4000 IU group. Higher 25(OH)D concentrations did not alter cord blood calcium or phosphorus. The study suffered from a high dropout rate, while powered only for a biochemical endpoint. However, by combining all available randomized data so far, a reduced OR of pre-eclampsia is evident in supplemented women with a pooled OR of 0.66 (95% CI 0.52 -0.83, p = 0.001) [START_REF] Aghajafari | Association between maternal serum 25-hydroxyvitamin D level and pregnancy and neonatal outcomes: systematic review and meta-analysis of observational studies[END_REF].

Gestational diabetes mellitus

Although some observational studies support an association between maternal hypovitaminosis D during pregnancy and the development of GDM [START_REF] Baker | First trimester maternal vitamin D status and risk for gestational diabetes mellitus: a nested case-control study[END_REF][START_REF] Zhang | Maternal plasma 25-hydroxyvitamin D concentrations and the risk for gestational diabetes mellitus[END_REF][START_REF] Parlea | Association between serum 25-hydroxyvitamin D in early pregnancy and risk of gestational diabetes mellitus[END_REF], data from supplementation studies are limited. A double-blinded, randomized controlled trial (RCT) in 54 women diagnosed with GDM reported an improvement in fasting glucose and Homeostasis Model Assessment-Insulin Resistance (HOMA-IR) index after two doses of oral 50,000 IU vitamin D, given 21 days apart, compared with placebo [START_REF] Soheilykhah | The effect of different doses of vitamin D supplementation on insulin resistance during pregnancy[END_REF]. However, significant differences in these parameters were noted at baseline, making the results difficult to interpret. In an open label RCT of vitamin D supplementation in two groups of Pakistani women, 4,000 IU of vitamin D were administered compared to calcium and ferrous sulphate supplementation [START_REF] Hossain | Obstetric and neonatal outcomes of maternal vitamin D supplementation: Results of an open label randomized controlled trial of antenatal vitamin D supplementation in Pakistani women[END_REF]. The obstetrical outcomes were identical in both groups. This effect was attributed to the inefficacy of the given vitamin D regimen to achieve normalization of maternal vitamin D status (only 15 % of pregnant women achieved concentrations above 30 ng/ml), leaving the majority in the deficiency range.

In an Australian double-blind controlled supplementation study [START_REF] Yap | Vitamin D supplementation and the effects on glucose metabolism during pregnancy: a randomized controlled trial[END_REF], a cohort of 209 pregnant women before 20 th gestational week were randomized in either 5,000 IU (n = 89) or 400 IU (n = 90) of oral vitamin D 3 daily, until delivery. Endpoints were maternal glucose concentrations in Oral Glucose Tolerance Test (OGTT, 26 th -28 th gestational week), neonatal 25(OH)D concentrations, obstetric and neonatal outcomes and assessment of maternal insulin resistance. Although an inverse association between baseline 25(OH)D and fasting and 2-h glucose concentrations was found in post hoc analysis, the 5,000 IU group failed to demonstrate significant differences in mean fasting, 2-h blood glucose concentrations and HOMA-IR, compared to the 400 IU group. Overall, all women in the 5,000 IU group which developed GDM (n = 7) manifested adequate vitamin D status at the time of diagnosis.

However, this study was not adequately powered to detect a difference between groups in the incidence of GDM.

In summary, as far as maternal outcomes are concerned, although supplementation studies homogeneously indicate a beneficial effect on the reduction of pre-eclampsia risk, the absence of pre-conception vitamin D values, the limited power and the heterogeneity in thresholds used do not allow for definitive conclusions to be drawn. In the case of GDM, risk reduction data do not indicate a beneficial effect, so far.

Fetal outcomes

Anthropometry at birth or during early life is the most studied extra-skeletal clinical outcome of maternal vitamin D supplementation. So far, only two [START_REF] Hollis | Vitamin D supplementation during pregnancy: double-blind, randomized clinical trial of safety and effectiveness[END_REF][START_REF] Yu | Vitamin D deficiency and supplementation during pregnancy[END_REF] out of six RCTs [START_REF] Hollis | Vitamin D supplementation during pregnancy: double-blind, randomized clinical trial of safety and effectiveness[END_REF][START_REF] Yu | Vitamin D deficiency and supplementation during pregnancy[END_REF][START_REF] Marya | Effect of vitamin D supplementation during pregnancy on foetal growth[END_REF][START_REF] Brooke | Vitamin D supplements in pregnant Asian women: effects on calcium status and fetal growth[END_REF][START_REF] Delvin | Vitamin D supplementation during pregnancy: effect on neonatal calcium homeostasis[END_REF][START_REF] Mallet | Vitamin D supplementation in pregnancy: a controlled trial of two methods[END_REF][START_REF] Roth | Maternal vitamin D3 supplementation during the third trimester of pregnancy: effects on infant growth in a longitudinal followup study in Bangladesh[END_REF] defined 25(OH)D concentrations as their primary outcome and had adequate sample size. The only study, which demonstrated effects on neonatal clinical parameters [START_REF] Marya | Effect of vitamin D supplementation during pregnancy on foetal growth[END_REF], was conducted in India, an area with profound vitamin D deficiency. Administration of two doses of 600,000 IU vitamin D in the third trimester of pregnancy resulted in a significant increase in birth weight of the offspring, compared to the non-supplemented group. This study did not define a primary outcome parameter, used no placebo and reported no data on 25(OH)D concentrations.

Anthropometry

In an effort to assess post-partum beneficial effects of optimization of maternal vitamin D status in offspring linear growth, a randomized, double-blind, supplementation trial [START_REF] Roth | Maternal vitamin D3 supplementation during the third trimester of pregnancy: effects on infant growth in a longitudinal followup study in Bangladesh[END_REF] (35,000 IU/week vs. placebo) during the first trimester of pregnancy evaluated longitudinally neonatal anthropometry from birth to 12 months of age. The primary analysis included evaluation of mean length-for-age Z-score based on international standards. At birth, no differences among the two groups were evident, whereas at one year of age, mean length-forage was higher in the supplemented group, in conjunction with an increase in longitudinal growth during early infancy, interpreted in an increase of 1.1 cm throughout the first year of life, after controlling for sex. A large-scale, supplementation study [START_REF] Hollis | Vitamin D supplementation during pregnancy: double-blind, randomized clinical trial of safety and effectiveness[END_REF]

Immune system

The effect of maternal vitamin D supplementation on offspring immune profile remains controversial. In a large cohort of more than 5,000 young adults [START_REF] Hypponen | Infant vitamin D supplementation and allergic conditions in adulthood: northern Finland birth cohort 1966[END_REF], supplementation with more than 2,000 IU vitamin D daily in the first year of life was found to be associated with an increased prevalence of allergic rhinitis. Although this trial centred on supplementation during infancy and not during pregnancy, it could comprise a spectrum of long-term effects of vitamin D equilibrium on immune regulation. This research question was the main objective in a RCT where 180 pregnant women were allocated randomly from 27 th gestational week to either, single bolus of 200.000 IU per os or 800 IU d of ergocalciferol daily [START_REF] Goldring | Prenatal vitamin d supplementation and child respiratory health: a randomised controlled trial[END_REF]. No significant effect of maternal supplementation was evident on the risk of offspring wheeze, atopy (assessed by skin test) or lung function at 3 years of age. It has to be noted, however, that the supplemented groups demonstrated inadequate vitamin D status at both dosing regimens (daily dose: 26 nmol/l, bolus dose: 25 nmol/l), an effect that might influence potential beneficial effects of vitamin D supplementation.

In summary, as far as fetal outcomes are concerned, supplementation studies indicate a potential beneficial effect on offspring anthropometry. However, several parameters regarding timing, duration and dose of supplementation regimen remain to be elucidated before incorporating this evidence into daily clinical practice.

Why data from supplementation studies fail to reveal favourable clinical outcomes?

Based on the data by the supplementation studies discussed above, a series of reasons can be implicated. These reasons are discussed in the following paragraphs and illustrated in Table 2.

Study design

It could be argued that the link between maternal hypovitaminosis D and adverse outcomes is not causative and that decreased vitamin D concentrations are a consequence or a confounder, rather than a disease per se. However, recent data on cardiovascular disease (CVD) risk ( 27

Vitamin D expenditure

Theoretically, serum vitamin D concentrations are the result of endogenous production and dietary intake [START_REF] Gray | The metabolism of vitamin D3 and 25-hydroxyvitamin D3 in normal and anephric humans[END_REF][START_REF] Smith | The turnover and transport of vitamin ,D and a polar metabolite with the properties of 25-hydroxycholecalciferol in human plasma[END_REF]. As a consequence, the potential beneficial effects of vitamin D supplementation should be interpreted in the context of attained concentrations of serum

Supplementation regimen

An ideal vitamin D supplementation trial in pregnancy would use a reference population, with different baseline vitamin D status, aiming at attaining sufficient serum 25(OH)D concentrations, in order to establish a "supplementation and result" relationship [START_REF] Heaney | Guidelines for optimizing design and analysis of clinical studies of nutrient effects[END_REF].

Nevertheless, this outcome could be significantly affected by the regimen and dose of vitamin D used in each study. Since even a large bolus of 50,000 or 100,000 IU of vitamin D would rapidly (in a few days) be absorbed and undetectable from the serum [START_REF] Hollis | Clinical review: The role of the parent compound vitamin D with respect to metabolism and function: Why clinical dose intervals can affect clinical outcomes[END_REF]. It has to be noted that several supplementation trials used this type of bolus administration, with a potential effect on their outcomes [START_REF] Yu | Vitamin D deficiency and supplementation during pregnancy[END_REF][START_REF] Mallet | Vitamin D supplementation in pregnancy: a controlled trial of two methods[END_REF]. In this context, the duration of supplementation could also play a role in maintaining adequate vitamin D concentrations. Although the optimal dosing and duration for specific outcomes remains to be defined, by supplying constant doses of vitamin D for 3 -4 months, a steady state will be attained [START_REF] Vieth | Efficacy and safety of vitaminD3 intake exceeding the lowest observed adverse effect level[END_REF][START_REF] Heaney | Human serum 25hydroxycholecalciferol response to extended oral dosing with cholecalciferol[END_REF]. This is not the case in bolus regimens with monthly or weekly patterns of supplementation. The short duration of vitamin D supplementation during pregnancy (i.e. weeks or months) may also not be adequate to alter the pathogenetic pathways in which vitamin D is speculated to be involved, such as in pre-eclampsia and GDM states. Thus, supplementation before pregnancy and achievement of vitamin D sufficiency may be more effective than supplementation during pregnancy for both maternal and fetal outcomes.

Geographical characteristics

As vitamin D is generated by an environmental factor (sunshine exposure), it can be affected by geographical factors [START_REF] Karras | Maternal vitamin D status during pregnancy: the Mediterranean reality[END_REF][START_REF] Mulligan | Implications of vitamin D deficiency in pregnancy and lactation[END_REF]. Reports from Europe, USA and Africa indicate that populations from different countries share more common vitamin D-related characteristics than cohorts from the same country [START_REF] Prentice | Vitamin D Deficiency and its health consequences in Africa[END_REF][START_REF] Kaushal | Vitamin D in pregnancy: A metabolic outlook[END_REF]. This concept is further supported by Kimlin et al. [START_REF] Kimlin | Location and vitamin D synthesis: is the hypothesis validated by geophysical data?[END_REF], who assessed vitamin D data from seven USA locations. During eight months (March to October), no latitude gradient (from 18° to 44°N) of vitamin D was observed. In contrast, during cooler months (November to February) vitamin D was strongly determined by latitude. These observations indicate that vitamin D could vary significantly within a country, particularly in areas with a wide range of latitude gradient. Moreover, vitamin D status of immigrant populations in Europe was poor compared with that of the indigenous European populations [START_REF] Van Der Meer | Prevalence of vitamin D deficiency among Turkish, Moroccan, Indian and sub-Sahara African populations in Europe and their countries of origin: an overview[END_REF], indicating that social and cultural habits are different as well. Indeed, the approach to vitamin D status taking into account specific geographical characteristics, such as latitude, ultra-violet B (UVB) radiation and microclimate, as well as the specific social and dietary habits, could minimize heterogeneity among studies.

Metabolism during pregnancy

Vitamin D and calcium equilibrium are altered during pregnancy compared with the nonpregnant state [START_REF] Kovacs | Vitamin D in pregnancy and lactation: maternal, fetal, and neonatal outcomes from human and animal studies[END_REF]. Pregnant women manifest extremely high concentrations of 1,25(OH) 2 D without evidence of hypercalcemia, whereas vitamin D-binding protein (VDBP) concentrations increase in response to high estrogen concentrations [START_REF] Ardawi | Calcium-regulating hormones and parathyroid hormone-related peptide in normal human pregnancy and postpartum: a longitudinal study[END_REF]. VDBP is increasingly recognized as a vital parameter in the interpretation of vitamin D status [START_REF] Rousseau | Critical care and vitamin D status assessment: what about immunoassays and calculated free 25OH-D?[END_REF].

Assay methodology

Although the existence of various vitamin D forms, such as epimers, has been established, their clinical significance remains obscure. Most report on a minority of vitamin D metabolites, which are usually the circulating ones. The latter are convenient to be measured, but they are essentially inactive. Furthermore, recent data show that at least one epimer form has activity in vitro [START_REF] Karras | An observational study reveals that neonatal vitamin D is primarily determined by maternal contributions: Implications of a new assay on the roles of vitamin D forms[END_REF]. In studies where both the active and circulating forms have been measured, there was no significant correlation between them. Indeed, a recent study has revealed that higher concentrations of the active form exist in diseases, such rheumatoid arthritis, and diabetes mellitus type 1 [START_REF] Shah | Low 25OH vitamin D2 levels found in untreated Alzheimer's patients, compared to acetylcholinesterase-inhibitor treated and controls[END_REF]. In recent years, there have been considerable advances in techniques for vitamin D measurement [START_REF] Shah | Misleading measures in Vitamin D analysis: A novel LC-MS/MS assay to account for epimers and isobars[END_REF][START_REF] Shah | Method for simultaneous analysis of eight analogues of vitamin D using liquid chromatography tandem mass spectrometry[END_REF]. High quality assays for multiple vitamin D forms include liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) [START_REF] Shah | Exploring the role of vitamin D in type 1 diabetes, rheumatoid arthritis and Alzheimer's disease: new insights from accurate analysis of ten forms[END_REF][START_REF] Naughton | Vitamin D status and ill health[END_REF]. With the development of more advanced assays, a thorough understanding of the interplay among the various vitamin D forms can be achieved. The accurate assay highlights a considerable proportion of vitamin D exists as epimers and there is a lack of correlation between the circulating and active forms. These results underscore the need for accurate measurements to appraise vitamin D status. The results, based on specific and accurate measurement, revealed that maternal characteristics and active forms of vitamin D, along with their epimers explain 56% of neonatal vitamin D concentration [START_REF] Karras | An observational study reveals that neonatal vitamin D is primarily determined by maternal contributions: Implications of a new assay on the roles of vitamin D forms[END_REF].

  treated 257 pregnant women with 400, 2,000 or 4,000 IU of vitamin D 3 daily during pregnancy. Achieved cord blood 25(OH)D concentrations were 45.5 ± 25.3 nmol/l in the low-dose group and 66.3 ± 25.8 nmol/l in the high-dose group. A positive association between vitamin D dose and neonatal weight percentile, as well as a negative association between 25(OH)D concentrations and premature labour and infection was evident. These results might have been biased by the small study sample (n = 162, supplemented until term) and the high percentage of maternal vitamin D deficiency (35%) in the group supplemented with 4,000 IU daily.

  ), suggest a causal association between serum 25(OH)D concentrations and CVD risk, as do most well-designed RCTs. The term "well-designed RCT" is of utmost importance in understanding the potential beneficial effects of vitamin D supplementation during pregnancy. As described recently by Heaney (28), a vitamin D RCT should focus on a specific outcome, enrol only participants with low 25(OH)D concentrations and supplement with appropriate doses and regimens of vitamin D 3 .

25 (

 25 OH)D and not just the dose administered. Vitamin D supplementation markedly differs from other interventions, where a pharmaceutical compound is given. In the former case, serum 25(OH)D concentrations are under the confounding contribution of newly synthesized 25(OH)D, whereas in the latter, serum / plasma concentrations depend on the administered dose (29). This phenomenon is of particular importance in defining the vitamin D doseresponse relationship in supplementation trials. Thus, incorporation of vitamin D expenditure parameters, such as 25(OH)D plasma half-life, could provide an additional insight to supplementation studies, by identifying vitamin D kinetics (e.g. storage and release from fat and muscle) (31).

  Recently, results from a large study in community-dwelling black Americans, demonstrated low concentrations of total 25(OH)D and VDBP compared to white population, resulting in similar concentrations of estimated bioavailable 25(OH)D[START_REF] Powe | Vitamin D-binding protein and vitamin D status of black Americans and white Americans[END_REF]. Although the assay methodology used in this was prone to overestimation of bio-available 25-hydroxyvitamin D by 2 to 2.5 times owing to underestimation of vitamin D-binding protein in black people, racial differences could theoretically explain these findings. Conversely, the increase in VDBP during pregnancy could decrease bioavailable vitamin D, albeit concentrations considered as normal according to current vitamin D criteria. These adaptive changes of vitamin D metabolism during pregnancy could interpret attained vitamin D concentrations, as optimal, although not. Interpreting bioavailable vitamin D concentrations in future trials in conjunction with VDBP concentrations could offer a new insight in the field. In addition, maternal vitamin D receptor (VDR) polymorphisms have been associated with an increase risk of GDM in Iranian population, as well as increased birth weight[START_REF] Aslani | VDR FokI polymorphism and its potential role in the pathogenesis of gestational diabetes mellitus and its complications[END_REF].

Data from supplementation trials with vitamin D during pregnancy fail to reveal a significant impact on maternal and offspring health, at least in consistent way. Possible reasons for this fact may include: Supplementation with a biomolecule that also derives from endogenous production and undergoes significant transformation in order to accomplish its skeletal and extra-skeletal actions is a challenging task. By taking into account the whole spectrum of parameters that could affect vitamin D homeostasis during pregnancy, it can be concluded that supplementation regimens should be specifically tailored on each population, taking into account parameters such the ones suggested by this study.

ETHICAL APPROVAL (RESEARCH INVOLVING HUMAN PARTICIPANTS

AND/OR ANIMALS): not required due to type of manuscript (review) Informed consent : not required due to type of manuscript (review) Αll authors have contributed significantly in the preparation of the manuscript and all authors are in agreement with the content of the manuscript. The authors declare no conflict of interest. The present article is not submitted for publication elsewhere.


MD, PhD Olivier Beauchet
email: olivier.beauchet@mcgill.ca

MD Cédric Annweiler

PhD Michele L Callisaya

MD Anne-Marie De Cock

PhD Jorunn L Helbostad

MD i , Reto W Kressig

PhD Velandai Srikanth

PhD Jean-Paul Steinmetz

PhD Helena M Blumen

MD Joe Verghese

MD, PhD Gilles Allali

Poor Gait Performance and Prediction of Dementia: Results From a Meta-Analysis

Keywords: Epidemiology, gait disorders/ataxia, motor control, dementia

Background-Poor gait performance predicts risk of developing dementia. No structured critical evaluation has been conducted to study this association yet. The aim of this meta-analysis was to systematically examine the association of poor gait performance with incidence of dementia.

Methods-An English and French Medline search was conducted in June 2015, with no limit of date, using the medical subject headings terms "Gait" OR "Gait Disorders, Neurologic" OR "Gait Apraxia" OR "Gait Ataxia" AND "Dementia" OR "Frontotemporal Dementia" OR "Dementia, Multi-Infarct" OR "Dementia, Vascular" OR "Alzheimer Disease" OR "Lewy Body Disease" OR "Frontotemporal Dementia With Motor Neuron Disease" (Supplementary Concept). Poor gait performance was defined by standardized tests of walking, and dementia was diagnosed according to international consensus criteria. Four etiologies of dementia were identified: any dementia,

Both gait and cognitive disorders are frequent in the elderly with a prevalence reaching 50% among individuals aged 85 years and older. [START_REF] Verghese | Abnormality of gait as a predictor of non-Alzheimer's dementia[END_REF][START_REF] Alexander | Gait disorders in older adults[END_REF][START_REF] Odenheimer | Comparison of neurologic changes in 'successfully aging' persons vs the total aging population[END_REF][START_REF] Nutt | Classification of gait and balance disorders[END_REF] This association exceeds a simple accumulation with aging and relies on a causal relationship. [START_REF] Nutt | Classification of gait and balance disorders[END_REF][START_REF] Montero-Odasso | Gait and cognition: A complementary approach to understanding brain function and the risk of falling[END_REF] Cognitive dysfunction may result in gait disorders by disorganizing the highest levels of gait control. [START_REF] Montero-Odasso | Gait and cognition: A complementary approach to understanding brain function and the risk of falling[END_REF][START_REF] Seidler | Motor control and aging: Links to age-related brain structural, functional, and biochemical effects[END_REF][START_REF] Beauchet | Motor phenotype of decline in cognitive performance among community-dwellers without dementia: Population-based study and metaanalysis[END_REF] However, the chronological development of gait disorders caused by cognitive dysfunctions in the context of the progression of dementia and its clinical application have been poorly studied.

Identifying clinical markers that predict dementia is an important issue for the implementation of adapted care, better understanding of early brain disorganization, and, thus, for implications for preventive and symptomatic interventions. [START_REF] Dubois | Advancing research diagnostic criteria for Alzheimer's disease: The IWG-2 criteria[END_REF][START_REF] Morris | Harmonized diagnostic criteria for Alzheimer's disease: Recommendations[END_REF][START_REF] Cummings | International Work Group criteria for the diagnosis of Alzheimer disease[END_REF][START_REF] Anand | Therapeutics of Alzheimer's disease: Past, present and future[END_REF] The emergence of brain imaging and biological markers contributes extensively to the early diagnosis of dementia, [START_REF] Dubois | Advancing research diagnostic criteria for Alzheimer's disease: The IWG-2 criteria[END_REF][START_REF] Morris | Harmonized diagnostic criteria for Alzheimer's disease: Recommendations[END_REF][START_REF] Cummings | International Work Group criteria for the diagnosis of Alzheimer disease[END_REF] but the high expense limits their use, especially in primary care and community-dwelling populations. [START_REF] Handels | Early cost-utility analysis of general and cerebrospinal fluid-specific Alzheimer's disease biomarkers for hypothetical disease-modifying treatment decision in mild cognitive impairment[END_REF][START_REF] Matthews | Medical Research Council Cognitive Function and Ageing Collaboration. A two-decade comparison of prevalence of dementia in individuals aged 65 years and older from three geographical areas of England: Results of the Cognitive Function and Ageing Study I and II[END_REF][START_REF] Prince | The global prevalence of dementia: A systematic review and meta-analysis[END_REF] Recently, a syndrome combining cognitive complaint and slow gait speed, called the "motoric cognitive risk" (MCR) syndrome, has been associated with the occurrence of dementia. [START_REF] Verghese | Motoric cognitive risk syndrome and the risk of dementia[END_REF][START_REF] Verghese | Motoric cognitive risk syndrome: Multicountry prevalence and dementia risk[END_REF] The uniqueness of the MCR syndrome is that it does not rely on a complex evaluation or laboratory investigations and, thus, is easy to apply clinically with low costs in large populations. [START_REF] Verghese | Motoric cognitive risk syndrome: Multicountry prevalence and dementia risk[END_REF] This observation suggests that the assessment of gait performance may be useful for predicting dementia. [START_REF] Verghese | Abnormality of gait as a predictor of non-Alzheimer's dementia[END_REF][START_REF] Verghese | Motoric cognitive risk syndrome and the risk of dementia[END_REF][START_REF] Verghese | Motoric cognitive risk syndrome: Multicountry prevalence and dementia risk[END_REF][START_REF] Alves | Changes in motor subtype and risk for incident dementia in Parkinson's disease[END_REF][START_REF] Abbott | Walking and dementia in physically capable elderly men[END_REF][START_REF] Van Kan | Gait speed, body composition, and dementia. The EPIDOS-Toulouse cohort[END_REF][START_REF] Aggarwal | Motor dysfunction in mild cognitive impairment and the risk of incident Alzheimer disease[END_REF][START_REF] Ramakers | Symptoms of preclinical dementia in general practice up to five years before dementia diagnosis[END_REF][START_REF] Verghese | Quantitative gait dysfunction and risk of cognitive decline and dementia[END_REF][START_REF] Verghese | High risk neurological gait syndrome and vascular dementia[END_REF][START_REF] Waite | Gait slowing as a predictor of incident dementia: 6-year longitudinal data from the Sydney Older Persons Study[END_REF][START_REF] Wang | Performance-based physical function and future dementia in older people[END_REF] At this time, no systematic critical evaluation of studies that have examined the association of poor gait performance and the occurrence of dementia has been performed, making it unclear whether poor gait performance can be used as an accurate predictor of dementia. Thus, we performed a systematic review and meta-analysis with the aim to qualitatively and quantitatively synthesize the association of poor gait performance with incidence of dementia.

Methods

Search Strategy and Data Extraction

A systematic search was conducted in June 2015 with no time limit for all English and non-English articles in Medline (PubMed) and EMBASE (Ovid, EMBASE). Following medical subject heading terms "Gait" OR "Gait Disorders, Neurologic" OR "Gait Apraxia" OR "Gait Ataxia" AND "Dementia" OR "Frontotemporal Dementia" OR "Dementia, Multi-Infarct" OR "Dementia, Vascular" OR "Alzheimer Disease" OR "Lewy Body Disease" OR "Frontotemporal Dementia With Motor Neuron Disease" (Supplementary Concept) were used. Additional studies, not captured by the electronic database search, were identified by contacting experts and searching reference lists of extracted papers. Two authors (OB and GA) independently conducted data extraction. A consensus procedure was developed but was not necessary because of concordance.

Study Selection

To be included in the primary analysis, selection criteria were (1) human study, (2) article published in English or French, (3) original study, (4) data collection of gait performance, (5) dementia used as outcome, and ( 6) prospective cohort design with information on the occurrence of dementia during the follow-up period. If a study met the initial selection criteria or its eligibility could not be determined from the title and abstract (or abstract not provided), the full text was retrieved. Two reviewers (OB and GA) then independently assessed the full text for inclusion status. Disagreements were resolved by a third reviewer (CA). The full articles were screened using the Strengthening the Reporting of Observational Studies in Epidemiology checklist, which describes items that should be included in reports of cohort studies. [START_REF] Von Elm | The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: Guidelines for reporting observational studies[END_REF] Furthermore, the quality of each study included in the meta-analysis was assessed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist and the Newcastle-Ottawa Scale. [START_REF] Liberati | The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: Explanation and elaboration[END_REF][START_REF] Wells | nonrandomised studies in meta-analyses[END_REF] Final selection of criteria was, therefore, applied when at baseline assessment participants were free of dementia and when the prediction was about dementia. The study selection procedure is presented in the PRISMA flow diagram [START_REF] Liberati | The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: Explanation and elaboration[END_REF] (Figure 1).

Qualitative Analysis

Of the 796 identified abstracts, 19 (2.4%) met the initial inclusion criteria. [START_REF] Verghese | Abnormality of gait as a predictor of non-Alzheimer's dementia[END_REF][START_REF] Verghese | Motoric cognitive risk syndrome and the risk of dementia[END_REF][START_REF] Verghese | Motoric cognitive risk syndrome: Multicountry prevalence and dementia risk[END_REF][START_REF] Alves | Changes in motor subtype and risk for incident dementia in Parkinson's disease[END_REF][START_REF] Abbott | Walking and dementia in physically capable elderly men[END_REF][START_REF] Van Kan | Gait speed, body composition, and dementia. The EPIDOS-Toulouse cohort[END_REF][START_REF] Aggarwal | Motor dysfunction in mild cognitive impairment and the risk of incident Alzheimer disease[END_REF][START_REF] Ramakers | Symptoms of preclinical dementia in general practice up to five years before dementia diagnosis[END_REF][START_REF] Verghese | Quantitative gait dysfunction and risk of cognitive decline and dementia[END_REF][START_REF] Verghese | High risk neurological gait syndrome and vascular dementia[END_REF][START_REF] Waite | Gait slowing as a predictor of incident dementia: 6-year longitudinal data from the Sydney Older Persons Study[END_REF][START_REF] Wang | Performance-based physical function and future dementia in older people[END_REF][START_REF] Buchman | Combinations of motor measures more strongly predict adverse health outcomes in old age: The rush memory and aging project, a communitybased cohort study[END_REF][START_REF] Tolea | Trajectory of mobility decline by type of dementia[END_REF][START_REF] Tolea | Longitudinal associations between physical and cognitive performance among community-dwelling older adults[END_REF][START_REF] Buracchio | The trajectory of gait speed preceding mild cognitive impairment[END_REF][START_REF] Camicioli | Motor slowing precedes cognitive impairment in the oldest old[END_REF][START_REF] Marquis | Independent predictors of cognitive decline in healthy elderly persons[END_REF][START_REF] Mielke | Assessing the temporal relationship between cognition and gait: Slow gait predicts cognitive decline in the Mayo Clinic Study of Aging[END_REF] After examination, we excluded 7 of those 19 studies because gait performance was included in a global motor score, [START_REF] Buchman | Combinations of motor measures more strongly predict adverse health outcomes in old age: The rush memory and aging project, a communitybased cohort study[END_REF][START_REF] Tolea | Trajectory of mobility decline by type of dementia[END_REF][START_REF] Tolea | Longitudinal associations between physical and cognitive performance among community-dwelling older adults[END_REF] prediction concerned mild cognitive impairment (MCI), and not dementia, [START_REF] Buracchio | The trajectory of gait speed preceding mild cognitive impairment[END_REF][START_REF] Camicioli | Motor slowing precedes cognitive impairment in the oldest old[END_REF][START_REF] Marquis | Independent predictors of cognitive decline in healthy elderly persons[END_REF] and 1 study focused on cognitive decline and not cognitive status. [START_REF] Mielke | Assessing the temporal relationship between cognition and gait: Slow gait predicts cognitive decline in the Mayo Clinic Study of Aging[END_REF] The remaining 12 studies were included in the systematic review and meta-analysis [START_REF] Verghese | Abnormality of gait as a predictor of non-Alzheimer's dementia[END_REF][START_REF] Verghese | Motoric cognitive risk syndrome and the risk of dementia[END_REF][START_REF] Verghese | Motoric cognitive risk syndrome: Multicountry prevalence and dementia risk[END_REF][START_REF] Alves | Changes in motor subtype and risk for incident dementia in Parkinson's disease[END_REF][START_REF] Abbott | Walking and dementia in physically capable elderly men[END_REF][START_REF] Van Kan | Gait speed, body composition, and dementia. The EPIDOS-Toulouse cohort[END_REF][START_REF] Aggarwal | Motor dysfunction in mild cognitive impairment and the risk of incident Alzheimer disease[END_REF][START_REF] Ramakers | Symptoms of preclinical dementia in general practice up to five years before dementia diagnosis[END_REF][START_REF] Verghese | Quantitative gait dysfunction and risk of cognitive decline and dementia[END_REF][START_REF] Verghese | High risk neurological gait syndrome and vascular dementia[END_REF][START_REF] Waite | Gait slowing as a predictor of incident dementia: 6-year longitudinal data from the Sydney Older Persons Study[END_REF][START_REF] Wang | Performance-based physical function and future dementia in older people[END_REF] Articles selected for the full review had the following information extracted: last name of authors and date of publication; country, name, and design of study, participant generic information (ie, setting, number of participants and proportion of women); age, cognitive status, and gait measures at baseline assessment; length of follow-up period; incident cases of dementia including number of individuals and etiology; and main results.

Meta-Analysis

The association between poor gait performance and occurrence of dementia was determined using the adjusted hazard ratio (HR), the adjusted relative risk (RR,) or the adjusted odds ratio (OR) for dementia with a 95% confidence interval (95% CI). In all cases, the longest follow-up period was used to calculate HR, RR, and OR, and only adjusted values of participant's baseline characteristics were used. The analyses used different outcomes: any dementia, Alzheimer disease (AD), vascular dementia (VaD), and non-AD (ie, pooling VaD, mixed dementias, and other dementias) for the dependent variables, and poor gait performance, estimated from gait score or gait speed, as independent variables. Poor gait performance was defined by standardized tests based on clinical gait assessment of distance walked on a defined distance or per day. Dementia was diagnosed according to the established international consensus criteria. Fixed effects meta-analyses were performed on the estimates to generate summary values. Results are presented as forest plots. Heterogeneity between studies was assessed using Cochrane χ 2 test for homogeneity, and the amount of variation because of heterogeneity was estimated by calculating the I 2 . [START_REF] Abramson | WINPEPI updated: Computer programs for epidemiologists, and their teaching potential[END_REF] Statistical analyses were performed using the software program WINPEPI Computer Programs for Epidemiologists (v 11.48). [START_REF] Higgins | Quantifying heterogeneity in a meta-analysis[END_REF]

Results

Table 1 summarizes the 12 studies included in this review. [START_REF] Verghese | Abnormality of gait as a predictor of non-Alzheimer's dementia[END_REF][START_REF] Verghese | Motoric cognitive risk syndrome and the risk of dementia[END_REF][START_REF] Verghese | Motoric cognitive risk syndrome: Multicountry prevalence and dementia risk[END_REF][START_REF] Alves | Changes in motor subtype and risk for incident dementia in Parkinson's disease[END_REF][START_REF] Abbott | Walking and dementia in physically capable elderly men[END_REF][START_REF] Van Kan | Gait speed, body composition, and dementia. The EPIDOS-Toulouse cohort[END_REF][START_REF] Aggarwal | Motor dysfunction in mild cognitive impairment and the risk of incident Alzheimer disease[END_REF][START_REF] Ramakers | Symptoms of preclinical dementia in general practice up to five years before dementia diagnosis[END_REF][START_REF] Verghese | Quantitative gait dysfunction and risk of cognitive decline and dementia[END_REF][START_REF] Verghese | High risk neurological gait syndrome and vascular dementia[END_REF][START_REF] Waite | Gait slowing as a predictor of incident dementia: 6-year longitudinal data from the Sydney Older Persons Study[END_REF][START_REF] Wang | Performance-based physical function and future dementia in older people[END_REF] All studies were published over the last 13 years. Seven studies were conducted in the United States. [START_REF] Verghese | Abnormality of gait as a predictor of non-Alzheimer's dementia[END_REF][START_REF] Verghese | Motoric cognitive risk syndrome and the risk of dementia[END_REF][START_REF] Abbott | Walking and dementia in physically capable elderly men[END_REF][START_REF] Aggarwal | Motor dysfunction in mild cognitive impairment and the risk of incident Alzheimer disease[END_REF][START_REF] Verghese | Quantitative gait dysfunction and risk of cognitive decline and dementia[END_REF][START_REF] Verghese | High risk neurological gait syndrome and vascular dementia[END_REF][START_REF] Wang | Performance-based physical function and future dementia in older people[END_REF] The 4 other studies were conducted in Norway, [START_REF] Alves | Changes in motor subtype and risk for incident dementia in Parkinson's disease[END_REF] France, [START_REF] Van Kan | Gait speed, body composition, and dementia. The EPIDOS-Toulouse cohort[END_REF] The Netherlands, [START_REF] Ramakers | Symptoms of preclinical dementia in general practice up to five years before dementia diagnosis[END_REF] and Australia. [START_REF] Waite | Gait slowing as a predictor of incident dementia: 6-year longitudinal data from the Sydney Older Persons Study[END_REF] One study combined cohorts from different countries. [START_REF] Verghese | Motoric cognitive risk syndrome: Multicountry prevalence and dementia risk[END_REF] The number of participants ranged from 171 [START_REF] Alves | Changes in motor subtype and risk for incident dementia in Parkinson's disease[END_REF] to 3855, [START_REF] Verghese | Motoric cognitive risk syndrome: Multicountry prevalence and dementia risk[END_REF] with 0% 18 to 100% [START_REF] Van Kan | Gait speed, body composition, and dementia. The EPIDOS-Toulouse cohort[END_REF] women. All participants were older adults at baseline, aged from ≥60 [START_REF] Verghese | Motoric cognitive risk syndrome: Multicountry prevalence and dementia risk[END_REF][START_REF] Alves | Changes in motor subtype and risk for incident dementia in Parkinson's disease[END_REF] to ≥75 [START_REF] Verghese | Abnormality of gait as a predictor of non-Alzheimer's dementia[END_REF][START_REF] Van Kan | Gait speed, body composition, and dementia. The EPIDOS-Toulouse cohort[END_REF][START_REF] Verghese | High risk neurological gait syndrome and vascular dementia[END_REF][START_REF] Waite | Gait slowing as a predictor of incident dementia: 6-year longitudinal data from the Sydney Older Persons Study[END_REF] years. Data collection was based on observational studies with longitudinal prospective cohort design, except in 1 study, which used a retrospective case-control design. [START_REF] Ramakers | Symptoms of preclinical dementia in general practice up to five years before dementia diagnosis[END_REF] At baseline, all participants were free of dementia. [START_REF] Verghese | Abnormality of gait as a predictor of non-Alzheimer's dementia[END_REF][START_REF] Verghese | Motoric cognitive risk syndrome and the risk of dementia[END_REF][START_REF] Verghese | Motoric cognitive risk syndrome: Multicountry prevalence and dementia risk[END_REF][START_REF] Alves | Changes in motor subtype and risk for incident dementia in Parkinson's disease[END_REF][START_REF] Abbott | Walking and dementia in physically capable elderly men[END_REF][START_REF] Van Kan | Gait speed, body composition, and dementia. The EPIDOS-Toulouse cohort[END_REF][START_REF] Aggarwal | Motor dysfunction in mild cognitive impairment and the risk of incident Alzheimer disease[END_REF][START_REF] Ramakers | Symptoms of preclinical dementia in general practice up to five years before dementia diagnosis[END_REF][START_REF] Verghese | Quantitative gait dysfunction and risk of cognitive decline and dementia[END_REF][START_REF] Verghese | High risk neurological gait syndrome and vascular dementia[END_REF][START_REF] Waite | Gait slowing as a predictor of incident dementia: 6-year longitudinal data from the Sydney Older Persons Study[END_REF][START_REF] Wang | Performance-based physical function and future dementia in older people[END_REF] Two studies included participants with MCI, [START_REF] Aggarwal | Motor dysfunction in mild cognitive impairment and the risk of incident Alzheimer disease[END_REF][START_REF] Wang | Performance-based physical function and future dementia in older people[END_REF] 2 studies included participants with MCR, [START_REF] Verghese | Motoric cognitive risk syndrome and the risk of dementia[END_REF][START_REF] Verghese | Motoric cognitive risk syndrome: Multicountry prevalence and dementia risk[END_REF] and 1 study selected participants with Parkinson disease (PD). Gait speed at usual pace at baseline assessment was used as the main outcome in 6 studies. [START_REF] Verghese | Motoric cognitive risk syndrome and the risk of dementia[END_REF][START_REF] Verghese | Motoric cognitive risk syndrome: Multicountry prevalence and dementia risk[END_REF][START_REF] Van Kan | Gait speed, body composition, and dementia. The EPIDOS-Toulouse cohort[END_REF][START_REF] Aggarwal | Motor dysfunction in mild cognitive impairment and the risk of incident Alzheimer disease[END_REF][START_REF] Waite | Gait slowing as a predictor of incident dementia: 6-year longitudinal data from the Sydney Older Persons Study[END_REF][START_REF] Wang | Performance-based physical function and future dementia in older people[END_REF] In 3 of them, the gait speed value was categorized using quartile segmentation, and a scaled score was built from slowest to fastest gait speed. [START_REF] Van Kan | Gait speed, body composition, and dementia. The EPIDOS-Toulouse cohort[END_REF][START_REF] Aggarwal | Motor dysfunction in mild cognitive impairment and the risk of incident Alzheimer disease[END_REF][START_REF] Wang | Performance-based physical function and future dementia in older people[END_REF] Clinical gait abnormalities were used as the predictor in three studies. [START_REF] Verghese | Abnormality of gait as a predictor of non-Alzheimer's dementia[END_REF][START_REF] Alves | Changes in motor subtype and risk for incident dementia in Parkinson's disease[END_REF][START_REF] Ramakers | Symptoms of preclinical dementia in general practice up to five years before dementia diagnosis[END_REF] In the first study, they corresponded to falls and problems with walking. [START_REF] Ramakers | Symptoms of preclinical dementia in general practice up to five years before dementia diagnosis[END_REF] In the second study, clinical gait abnormalities were rated as unsteady gait, frontal gait, hemiparetic gait, neuropathic gait, ataxic gait, parkinsonian gait, and spastic gait. [START_REF] Verghese | Abnormality of gait as a predictor of non-Alzheimer's dementia[END_REF] In the third one, clinical gait abnormalities were based on an abnormal score for the gait items of Unified Parkinson Disease Rating Scale subscales II and III. [START_REF] Alves | Changes in motor subtype and risk for incident dementia in Parkinson's disease[END_REF] In 1 study, poor gait performance combined slow gait speed and extrapyramidal symptoms (based on the presence of bradykinesia, rigidity, and tremor) [START_REF] Waite | Gait slowing as a predictor of incident dementia: 6-year longitudinal data from the Sydney Older Persons Study[END_REF] ; while in the other one, they were defined as the presence of hemiparetic, frontal, or unsteady gait. [START_REF] Verghese | High risk neurological gait syndrome and vascular dementia[END_REF] Abnormalities in pace, rhythm, and variability were used to define poor gait performance in 1 study. [START_REF] Verghese | Quantitative gait dysfunction and risk of cognitive decline and dementia[END_REF] In addition, in another study, the distance walked per day expressed in miles and separated in 4 levels from <0.25 (ie, lowest) to >2 (highest) miles was used for defining poor gait performance. The length of follow-up ranged from 3 15 to 9 years. In 5 studies, incidental cases of the 5 subgroups of dementia were recorded (ie, any dementia, AD, non-AD, VaD, mixed, and other dementias). Any dementia was recorded in 2 studies [START_REF] Ramakers | Symptoms of preclinical dementia in general practice up to five years before dementia diagnosis[END_REF][START_REF] Waite | Gait slowing as a predictor of incident dementia: 6-year longitudinal data from the Sydney Older Persons Study[END_REF] and AD [START_REF] Aggarwal | Motor dysfunction in mild cognitive impairment and the risk of incident Alzheimer disease[END_REF] and VaD 23 in 1 study. One study recorded AD and any dementia, [START_REF] Verghese | Motoric cognitive risk syndrome: Multicountry prevalence and dementia risk[END_REF] whereas another one reported any dementia, AD, and VaD. [START_REF] Verghese | Quantitative gait dysfunction and risk of cognitive decline and dementia[END_REF] One study reported incidence of dementia in patients with PD. Incidence of dementia during the follow-up ranged from 6.5% [START_REF] Verghese | High risk neurological gait syndrome and vascular dementia[END_REF] to 52.9%. [START_REF] Alves | Changes in motor subtype and risk for incident dementia in Parkinson's disease[END_REF] Most studies found an association between poor gait performance and occurrence of any dementia, except in 2 studies. [START_REF] Verghese | Motoric cognitive risk syndrome and the risk of dementia[END_REF][START_REF] Wang | Performance-based physical function and future dementia in older people[END_REF] In a study by Verghese et al, [START_REF] Verghese | Motoric cognitive risk syndrome and the risk of dementia[END_REF] a nonsignificant association was reported for slow gait speed (excluding participants with MCR), whereas a significant association was found with MCR. The nonsignificant association reported in a study by Waite et al [START_REF] Waite | Gait slowing as a predictor of incident dementia: 6-year longitudinal data from the Sydney Older Persons Study[END_REF] was present for the follow-up at 6 years, but not at 3 years [OR 3.6 (1.2;10.3)]. Results were more controversial regarding AD onset. Four studies found a significant association, [START_REF] Verghese | Motoric cognitive risk syndrome: Multicountry prevalence and dementia risk[END_REF][START_REF] Abbott | Walking and dementia in physically capable elderly men[END_REF][START_REF] Aggarwal | Motor dysfunction in mild cognitive impairment and the risk of incident Alzheimer disease[END_REF][START_REF] Wang | Performance-based physical function and future dementia in older people[END_REF] whereas 3 studies did not. [START_REF] Verghese | Abnormality of gait as a predictor of non-Alzheimer's dementia[END_REF][START_REF] Verghese | Motoric cognitive risk syndrome and the risk of dementia[END_REF][START_REF] Verghese | Quantitative gait dysfunction and risk of cognitive decline and dementia[END_REF][START_REF] Wang | Performance-based physical function and future dementia in older people[END_REF] In a study by Aggarwal et al, [START_REF] Aggarwal | Motor dysfunction in mild cognitive impairment and the risk of incident Alzheimer disease[END_REF] both significant and nonsignificant associations were reported, when considering gait speed and Parkinson gait score. Gait disturbances were associated with the occurrence of VaD, except in 1 study. [START_REF] Abbott | Walking and dementia in physically capable elderly men[END_REF] For non-AD, a significant association was reported in 1 study, 1 whereas others found a nonsignificant association. [START_REF] Verghese | Motoric cognitive risk syndrome: Multicountry prevalence and dementia risk[END_REF][START_REF] Abbott | Walking and dementia in physically capable elderly men[END_REF] Finally, the highest HR value reported was 80.0 for PD dementia. [START_REF] Alves | Changes in motor subtype and risk for incident dementia in Parkinson's disease[END_REF] Figure 2 shows the forest plot of pooled HR and RR of incident dementias computed with meta-analysis technique. The pooled HR and RR was 1.53 (95% CI 1.42-1.65) with P value < .001 for any dementia,1.03 (95% CI 1.01-1.05) with P value = .004 for AD,1.89 (95% CI 1.60-2.22) with P value < .001 for non-AD, and 1.79 (95% CI 1. 51-2.12) with P value < . 001 for VaD. When pooling all values (ie, HR, RR, and OR), the overall value was 1.56 (95% CI 1.44-.68) with P value < .001 for any dementia (Figure 3).

Discussion

This systematic review and meta-analysis provide evidence that poor gait performance predicts dementia, especially when considering non-AD and VaD. Findings are more inconsistent for the prediction of AD; some studies showed a significant association whereas others did not, and the pooled effect for AD was weaker than that seen with non-AD dementias as the outcome.

The main findings of this meta-analysis confirm that poor gait performance predicts the occurrence of dementia after a long follow-up period. Poor gait performance, regardless of how it was defined, was present between 3 and 9 years before dementia was diagnosed, which provides evidence for a close relationship between gait and cognitive dysfunctions, and its directionality. Indeed, 92% of the studies were based on a longitudinal prospective cohort design providing information on the chronological but not causal relationship. Poor gait performance precedes clinical symptoms of dementia; this chronological association is especially due to brain lesions caused by vascular and/or neurodegenerative processes. [START_REF] Verghese | Abnormality of gait as a predictor of non-Alzheimer's dementia[END_REF] Indeed, there is increasing evidence that poor motor performance is caused by brain damage related to cognitive decline. [START_REF] Verghese | Abnormality of gait as a predictor of non-Alzheimer's dementia[END_REF][START_REF] Montero-Odasso | Gait and cognition: A complementary approach to understanding brain function and the risk of falling[END_REF][START_REF] Seidler | Motor control and aging: Links to age-related brain structural, functional, and biochemical effects[END_REF][START_REF] Beauchet | Motor phenotype of decline in cognitive performance among community-dwellers without dementia: Population-based study and metaanalysis[END_REF] These motor disorders lead to poor gait performance and gait instability, and are usually provoked by a disorganization of the brain regions involved in the highest levels of gait control at the onset of dementia. [START_REF] Montero-Odasso | Gait and cognition: A complementary approach to understanding brain function and the risk of falling[END_REF][START_REF] Seidler | Motor control and aging: Links to age-related brain structural, functional, and biochemical effects[END_REF][START_REF] Beauchet | Motor phenotype of decline in cognitive performance among community-dwellers without dementia: Population-based study and metaanalysis[END_REF] Recently, it has been reported, in a sample of 1719 participants (77.4 ± 7.3 years, 53.9% female) separated into cognitively healthy individuals, patients with amnestic and nonamnestic MCI, and patients with mild and moderate stages of AD and non-AD, that performance of spatiotemporal gait parameters declined in parallel to the stage of cognition, from MCI to moderate dementia. [START_REF] Allali | Gait phenotype from mild cognitive impairment to moderate dementia: Results from the GOOD initiative[END_REF] Gait parameters of patients with nonamnestic MCI were more disturbed compared with patients with amnestic MCI; MCI subgroups performed better than demented patients. [START_REF] Allali | Gait phenotype from mild cognitive impairment to moderate dementia: Results from the GOOD initiative[END_REF] Gait control depends largely on cognition [START_REF] Seidler | Motor control and aging: Links to age-related brain structural, functional, and biochemical effects[END_REF] ; disturbed cognitive performance is responsible for poorer gait performance and greater instability in patients with dementia or pre-dementia stages such as MCI or MCR, but also in cognitively healthy individuals. [START_REF] Verghese | Abnormality of gait as a predictor of non-Alzheimer's dementia[END_REF][START_REF] Montero-Odasso | Gait and cognition: A complementary approach to understanding brain function and the risk of falling[END_REF][START_REF] Seidler | Motor control and aging: Links to age-related brain structural, functional, and biochemical effects[END_REF][START_REF] Beauchet | Motor phenotype of decline in cognitive performance among community-dwellers without dementia: Population-based study and metaanalysis[END_REF][START_REF] Beauchet | Biology of gait control: Vitamin D involvement[END_REF] In particular, episodic memory and executive function have been separately associated with gait performance in the 2 latter categories of nondemented individuals. [START_REF] Ble | Executive function correlates with walking speed in older persons: The InCHIANTI study[END_REF][START_REF] Hausdorff | Walking is more like catching than tapping: Gait in the elderly as a complex cognitive task[END_REF][START_REF] Beauchet | Gait control: A specific subdomain of executive function?[END_REF] Thus, we suggest that, in the recruited samples composed of participants free of dementia, those with poor gait performance were those with most altered brain health and, thus, who were most exposed to dementia. Therefore, measures of gait performance could be a simple and accessible way to predict dementia in large populations compared with psychometric assessment, and morphologic and biologic biomarkers, [START_REF] Verghese | Motoric cognitive risk syndrome and the risk of dementia[END_REF][START_REF] Verghese | Motoric cognitive risk syndrome: Multicountry prevalence and dementia risk[END_REF] which is especially relevant for the early diagnosis of dementia in primary care or developing countries.

Our findings also show that the prediction of dementia depends on its subtype. Poor gait performance, particularly slow walking speed, predicted VaD with the third highest value reported (HR 3.46 and pooled HR 1.79). This strong association is likely to be related to abnormalities in white matter and basal ganglia that are frequently implicated in VaD. [START_REF] Rosso | Health ABC study. Higher step length variability indicates lower gray matter integrity of selected regions in older adults[END_REF][START_REF] Rosano | Magnetization transfer imaging, white matter hyperintensities, brain atrophy and slower gait in older men and women[END_REF][START_REF] Rosano | Gait variability is associated with sub-clinical brain vascular abnormalities in high-functioning older adults[END_REF] Recently, the strong association between VaD and mobility impairment was underscored. Indeed, Tolea et al [START_REF] Tolea | Trajectory of mobility decline by type of dementia[END_REF] reported that the specific etiology of dementia may play an important role in how rapidly one progresses to disability. They reported that non-AD dementias, in general, and VaD, in particular, were associated with a faster decline in physical functionality compared with AD and normal cognition in a longitudinal study of 766 older adults whose physical performance and cognitive status were assessed annually. In addition, it has also been shown that patients with non-AD dementia, including VaD, had worse gait performance than those with AD dementia. [START_REF] Allali | Gait phenotype from mild cognitive impairment to moderate dementia: Results from the GOOD initiative[END_REF] The highest value (HR 80.0) reported in the study focusing on PD supports the involvement of the basal ganglia, especially the dopaminergic pathway. In contrast, the prediction of AD remains more uncertain because of both conclusive and inconclusive associations, and of low significant pooled value of 1.03. Certain explanations could be related to the type of gait performance recorded in the studies selected in this meta-analysis (no common cut-off value for gait speed across the studies) or by the various inclusion criteria for age ranging from ≥60 to ≥75. In studies showing inconclusive associations, poor gait performance was usually defined clinically without reference to spatiotemporal and, thus, objective parameters (ie, unsteady gait, frontal gait, hemiparetic gait, neuropathic gait, ataxic gait, parkinsonian gait or spastic gait). Gait examination based on a clinical observation of health professionals has 2 main limitations: its subjectivity depending on the background and the experience of the person who performed the gait assessment that may lead to a poor inter-rater reliability; and its limited extent of information. Recently, it was reported that in older community-dwellers without dementia, higher (ie, worse) stride-to-stride variability of stride time (STV; gait cycle duration) was associated with lower (ie, worse) cognitive performance in episodic memory and executive function. [START_REF] Allali | Gait phenotype from mild cognitive impairment to moderate dementia: Results from the GOOD initiative[END_REF] The results of a meta-analysis confirmed this finding by underscoring that higher STV was related to both MCI and dementia. [START_REF] Allali | Gait phenotype from mild cognitive impairment to moderate dementia: Results from the GOOD initiative[END_REF] Thus, higher STV appears to be a motor phenotype of cognitive decline both before and during the course of dementia. Some potential limitations of this systematic review and metaanalysis should be considered. The inclusion of various ages, limited number of studies, different gait protocols employed in included studies (quantitative vs clinical), different lengths of respective follow-up, inclusion of older adults only from developed countries, and various proportions of women may limit the generalization of the present findings. In addition, it is important to consider that most of the studies included in the meta-analysis were performed by the same group; this may further limit extension of our results to the general population.

In conclusion, this systematic review and meta-analysis provides evidence that poor gait performance predicts dementia. The association depends on the type of dementia; poor gait performance more consistently predicts VaD than AD. The predictive value for AD remains uncertain because of mixed results and low value of HR (1.03). The exploration of the association between poor gait performance and dementia may improve our knowledge on the interaction of disorganization of brain functions with cognitive decline being more likely associated with the highest level of gait control. Perspectives on improving dementia prediction may rely on the use of more specific markers of the highest level of gait control such as the STV, or the combined use of measures of gait performance with other clinical markers of dementia such as cognitive performance. Forest plot of pooled estimated HR pooled with OR for risk of incident of any dementia in participants with abnormal gait at baseline compared with those with normal gait. Square box area proportional to the sample size of each study; horizontal lines corresponding to the 95% CI; diamond representing the summary value; vertical line corresponding to a HR combined with RR and OR of 1.00, equivalent to no difference.

Fig. 1 .

 1 Fig. 1. Flow diagram of selection of studies. *Ovid EMBASE.

Fig. 2 .

 2 Fig. 2. Forest plot of pooled estimated HR for risk of incident dementia. (A) Any dementia, (B) AD, (C) non-AD, and (D) VaD in participants with abnormal gait at baseline compared with those with normal gait. Square box area proportional to the sample size of each study; horizontal lines corresponding to the 95% CI; diamond representing the summary value; vertical line corresponding to a HR combined with RR of 1.00, equivalent to no difference.

Fig. 3 .

 3 Fig. 3.

J Am Med Dir Assoc. Author manuscript; available in PMC 2017 February 21.

Acknowledgments

We are grateful to the authors of the selected articles for providing additional data required for meta-analysis.

The statistical analysis was conducted by Olivier Beauchet, MD, PhD. G Allali is supported by a grant from the Geneva University Hospitals and the Resnick Gerontology Center, Albert Einstein College of Medicine, Yeshiva University.

The study was supported by "Biomathics." The sponsors had no role in the design and conduct of the study, in the collection, management, analysis, and interpretation of the data, or in the preparation, review, or approval of the manuscript

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