Matthieu Gallou-Guyot

Stéphane Mandigout

Laure Combourieu-Donnezan

Louis Bherer

Anaick Perrochon
email: anaick.perrochon@unilim.fr

Anaick Perrochon

PhD Anaïck Perrochon

Cognitive and physical impact of cognitive-motor dual-task training in cognitively impaired older adults: An overview

Keywords: Cognition, Cognitive impairment, Dementia, Dual-task training, Motor

ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Ageing is associated with cognitive decline, ranging from normal to pathological. This broad spectrum includes mild cognitive impairment (MCI), defined as a transient state between normal cognition and major neurocognitive disorders [START_REF] Sachdev | Classifying neurocognitive disorders: the DSM-5 approach[END_REF]. At the other end of this spectrum is dementia, the most common of which is Alzheimer's disease (AD) [START_REF]Alzheimer's Association. 2019 Alzheimer's disease facts and figures[END_REF].

Older adults with MCI present cognitive impairment [START_REF] Petersen | Mild cognitive impairment: a concept in evolution[END_REF] and sometimes additional physical impairment [START_REF] Boyle | Association of muscle strength with the risk of Alzheimer disease and the rate of cognitive decline in communitydwelling older persons[END_REF][START_REF] Makizako | The Association Between Decline in Physical Functioning and Atrophy of Medial Temporal Areas in Community-Dwelling Older Adults With Amnestic and Nonamnestic Mild Cognitive Impairment[END_REF]. These cognitive and physical impairments are risk factors for falls, loss of autonomy [START_REF] Shaw | Multifactorial intervention after a fall in older people with cognitive impairment and dementia presenting to the accident and emergency department: randomised controlled trial[END_REF], and progression to AD and other dementias [START_REF] Hughes | Should mild cognitive impairment be subtyped?[END_REF][START_REF] Roberts | Higher risk of progression to dementia in mild cognitive impairment cases who revert to normal[END_REF]. This is particularly true for older adults with motoric cognitive risk syndrome (MCR), characterized by dualdecline of both motor (slowed walking speed) [START_REF] Montero-Odasso | Dual decline in gait speed and cognition is associated with future dementia: evidence for a phenotype[END_REF][START_REF] Verghese | Motoric Cognitive Risk Syndrome and the Risk of Dementia[END_REF] and cognitive functions (similar to MCI) [START_REF] Verghese | Motoric Cognitive Risk Syndrome and the Risk of Dementia[END_REF].

Thus, many various programs have been developed to increase cognitive [START_REF] Baker | Effects of aerobic exercise on mild cognitive impairment: a controlled trial[END_REF][START_REF] Law | Effects of functional tasks exercise on older adults with cognitive impairment at risk of Alzheimer's disease: a randomised controlled trial[END_REF] and motor [START_REF] Chan | Efficacy of physical exercise in preventing falls in older adults with cognitive impairment: a systematic review and meta-analysis[END_REF] functions in older adults with MCI or dementias. These interventions consist of cognitive [START_REF] Law | Effects of functional tasks exercise on older adults with cognitive impairment at risk of Alzheimer's disease: a randomised controlled trial[END_REF] or physical [START_REF] Baker | Effects of aerobic exercise on mild cognitive impairment: a controlled trial[END_REF][START_REF] Chan | Efficacy of physical exercise in preventing falls in older adults with cognitive impairment: a systematic review and meta-analysis[END_REF] exercises. It has been assumed that the combination of cognitive and physical exercises (i.e., specifically designed simultaneous cognitive-motor dual-task (CMDT)) could maximize the effects [START_REF] Pichierri | Cognitive and cognitive-motor interventions affecting physical functioning: A systematic review[END_REF] and present greater benefits on cognitive [START_REF] Law | Effects of combined cognitive and exercise interventions on cognition in older adults with and without cognitive impairment: A systematic review[END_REF] and physical [START_REF] Pichierri | Cognitive and cognitive-motor interventions affecting physical functioning: A systematic review[END_REF] functions than cognitive or motor single task trainings in MCI.

Many recent systematic reviews have investigated the effects of CMDT with varied modalities on numerous cognitive or motor outcomes, reaching different conclusions [START_REF] Özbe | Immediate Intervention Effects of Standardized Multicomponent Group Interventions on People with Cognitive Impairment: A Systematic Review[END_REF][START_REF] Yang | Effectiveness of Combined Cognitive and Physical Interventions to Enhance Functioning in Older Adults With Mild Cognitive Impairment: A Systematic Review of Randomized Controlled Trials[END_REF]. Some reported positive effects on physical outcomes [START_REF] Yang | Effectiveness of Combined Cognitive and Physical Interventions to Enhance Functioning in Older Adults With Mild Cognitive Impairment: A Systematic Review of Randomized Controlled Trials[END_REF] while others reported CMDT as being ineffective on cognitive functions [START_REF] Özbe | Immediate Intervention Effects of Standardized Multicomponent Group Interventions on People with Cognitive Impairment: A Systematic Review[END_REF]. Furthermore, most intervention studies assessed feasibility, long-term effects and adherence, but this information seems unclear for CMDT in cognitively impaired older adults [START_REF] Gheysen | Physical activity to improve cognition in older adults: can physical activity programs enriched with cognitive challenges enhance the effects? A systematic review and metaanalysis[END_REF][START_REF] Karssemeijer | Positive effects of combined cognitive and physical exercise training on cognitive function in older adults with mild cognitive impairment or dementia: A meta-analysis[END_REF]. Data for CMDT have been summarized in a recent overview [START_REF] Gallou-Guyot | Effects of exergames and cognitive-motor dual-task training on cognitive, physical and dual-task functions in cognitively healthy older adults: an overview[END_REF], but only in cognitively healthy older adults. Inconsistent findings on CMDT in cognitively impaired older adults indicate the need for further studies. The present study aimed at 1) summarizing the effects of CMDT training on cognitive, physical and dual-task functions in cognitively impaired older adults, and 2) determining the feasibility (setting, need for supervision, safety), retention of benefits and adherence of these interventions.

Methods

Design and protocol

We used the definition of "systematic review" from a Cochrane guide [START_REF] Chandler | Cochrane Handbook for Systematic Review of Intervention version 5[END_REF]. In order to perform this overview, we used a protocol established prior to carrying out this review. The design and the protocol of this overview were established following authors' recommendations [START_REF] Pollock | What guidance is available for researchers conducting overviews of reviews of healthcare interventions? A scoping review and qualitative metasummary[END_REF], checklist [START_REF] Bougioukas | Preferred reporting items for overviews of systematic reviews including harms checklist: a pilot tool to be used for balanced reporting of benefits and harms[END_REF], Cochrane guidelines [START_REF] Pollock | Cochrane Handbook for Systematic Reviews of Interventions[END_REF] and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [START_REF] Moher | Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement[END_REF].

Search strategy

In order to gather the maximum amount of literature, and so as not to miss any reviews, we conducted our overview through different online databases: the Cochrane Database of Systematic Reviews, MEDLINE (PubMed search engine), Scopus, EMBASE, CINAHL, PsycINFO, ProQuest and SportDiscus. We also searched for grey literature through the reference list of included reviews. We performed the entire search to from February 1, 2020 to March 30, 2020. We searched the titles, keywords and abstracts of database entries by using a keyword search: cognitively impaired older adults AND cognitive-motor dual-task training AND physical OR cognitive OR dual-task functions (see details in Appendix A).

Eligibility criteria and selection

Two authors (MGG and AP) independently conducted the eligibility analysis and selection of reviews for inclusion in this overview. Concerning the study design, the inclusion criteria were systematic reviews or meta-analyses, including randomized controlled trials (RCTs) or non-randomized studies of interventions (NRSIs), and full scientific papers all written in English. To define the eligibility of a study's content, we used the PICO framework (Population, Intervention, Comparison, Outcome) [START_REF] Schardt | Utilization of the PICO framework to improve searching PubMed for clinical questions[END_REF]. The inclusion criteria were systematic reviews assessing as primary outcome the CMDT's effects on cognitive, physical or dual-task functions compared to active control groups or no intervention in cognitively impaired older adults. This included adults with MCI, MCR, dementia and AD. Active control groups were cognitive or motor trainings, or traditional interventions, i.e. supervised training programs following recommendations for the prevention of falls in older adults [START_REF] Chan | Efficacy of physical exercise in preventing falls in older adults with cognitive impairment: a systematic review and meta-analysis[END_REF]. The physical outcomes encompassed motor capacities (strength, gait, mobility and balance) and falls. The cognitive outcomes encompassed attention, memory and executive functions. The dual-task functions encompassed any combined cognitive and physical functions, performed simultaneously. The non-inclusion criteria were: i) non-systematic reviews; ii) reviews integrating participants with neurological disease other than dementia or MCI (e.g., stroke, Parkinson's disease, multiple sclerosis), young participants (below 60 years old), or healthy participants only; iii) reviews that only included motor dual-tasks, or sequential cognitivemotor training. After removing duplicates and scanning titles and abstracts, eligible studies were screened for inclusion by thorough reading.

Data extraction

Two authors (MGG and AP) independently extracted data from the reviews, including: number of primary studies included, objectives, populations, interventions, comparisons, outcomes, conclusion, and risk of bias. In case of disagreement or ambiguity, a third author decided (SM).

Study quality assessment

Two authors (MGG and AP) independently rated the methodology quality of the reviews included using the AMSTAR-2 critical appraisal tool [START_REF] Shea | AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both[END_REF], and any disagreements were resolved by consensus.

Overlap

The different systematic reviews included in this overview may have used the same primary studies, at least partially; this is called overlap. It is necessary to calculate the corrected covered area (CCA) [START_REF] Pieper | Systematic review finds overlapping reviews were not mentioned in every other overview[END_REF] to avoid the risk of interpretation and conclusion errors, giving disproportionate power to multiple primary studies.

Results

The initial database search revealed 4225 potentially relevant reviews. After duplicates were removed, 2544 titles and abstract were screened. A total of 95 reviews were assessed as full text, and 9 were included in this overview (Figure 1). The list of excluded reviews and reasons for exclusion are available in Appendix B. The nine reviews were published in the last six years [START_REF] Booth | Interventions incorporating physical and cognitive elements to reduce falls risk in cognitively impaired older adults: a systematic review[END_REF][START_REF] Bruderer-Hofstetter | Effective multicomponent interventions in comparison to active control and no interventions on physical capacity, cognitive function and instrumental activities of daily living in elderly people with and without mild impaired cognition -A systematic review and network metaanalysis[END_REF][START_REF] Gheysen | Physical activity to improve cognition in older adults: can physical activity programs enriched with cognitive challenges enhance the effects? A systematic review and metaanalysis[END_REF][START_REF] Karssemeijer | Positive effects of combined cognitive and physical exercise training on cognitive function in older adults with mild cognitive impairment or dementia: A meta-analysis[END_REF][START_REF] Law | Effects of combined cognitive and exercise interventions on cognition in older adults with and without cognitive impairment: A systematic review[END_REF][START_REF] Lipardo | Effect of Exercise and Cognitive Training on Falls and Fall-Related Factors in Older Adults With Mild Cognitive Impairment: A Systematic Review[END_REF][START_REF] Özbe | Immediate Intervention Effects of Standardized Multicomponent Group Interventions on People with Cognitive Impairment: A Systematic Review[END_REF][START_REF] Untari | A combination of cognitive training and physical exercise for elderly with the mild cognitive impairment: A systematic review[END_REF][START_REF] Yang | Effectiveness of Combined Cognitive and Physical Interventions to Enhance Functioning in Older Adults With Mild Cognitive Impairment: A Systematic Review of Randomized Controlled Trials[END_REF], including 5 reviews with additional metaanalysis [START_REF] Booth | Interventions incorporating physical and cognitive elements to reduce falls risk in cognitively impaired older adults: a systematic review[END_REF][START_REF] Bruderer-Hofstetter | Effective multicomponent interventions in comparison to active control and no interventions on physical capacity, cognitive function and instrumental activities of daily living in elderly people with and without mild impaired cognition -A systematic review and network metaanalysis[END_REF][START_REF] Gheysen | Physical activity to improve cognition in older adults: can physical activity programs enriched with cognitive challenges enhance the effects? A systematic review and metaanalysis[END_REF][START_REF] Karssemeijer | Positive effects of combined cognitive and physical exercise training on cognitive function in older adults with mild cognitive impairment or dementia: A meta-analysis[END_REF][START_REF] Untari | A combination of cognitive training and physical exercise for elderly with the mild cognitive impairment: A systematic review[END_REF]. The CCA value was 0.04, so the overlap can be considered as slight (see the details of overlap in Appendix C).

Figure 1: flow chart

Participants and interventions

The characteristics of the nine included systematic reviews are summarized in Table 1.

Interventions within reviews assessed cognitively impaired older adults only (i.e., with MCI, dementia or AD) [START_REF] Booth | Interventions incorporating physical and cognitive elements to reduce falls risk in cognitively impaired older adults: a systematic review[END_REF][START_REF] Karssemeijer | Positive effects of combined cognitive and physical exercise training on cognitive function in older adults with mild cognitive impairment or dementia: A meta-analysis[END_REF][START_REF] Lipardo | Effect of Exercise and Cognitive Training on Falls and Fall-Related Factors in Older Adults With Mild Cognitive Impairment: A Systematic Review[END_REF][START_REF] Özbe | Immediate Intervention Effects of Standardized Multicomponent Group Interventions on People with Cognitive Impairment: A Systematic Review[END_REF][START_REF] Yang | Effectiveness of Combined Cognitive and Physical Interventions to Enhance Functioning in Older Adults With Mild Cognitive Impairment: A Systematic Review of Randomized Controlled Trials[END_REF], or compared with cognitively healthy older adults [START_REF] Bruderer-Hofstetter | Effective multicomponent interventions in comparison to active control and no interventions on physical capacity, cognitive function and instrumental activities of daily living in elderly people with and without mild impaired cognition -A systematic review and network metaanalysis[END_REF][START_REF] Gheysen | Physical activity to improve cognition in older adults: can physical activity programs enriched with cognitive challenges enhance the effects? A systematic review and metaanalysis[END_REF][START_REF] Law | Effects of combined cognitive and exercise interventions on cognition in older adults with and without cognitive impairment: A systematic review[END_REF][START_REF] Untari | A combination of cognitive training and physical exercise for elderly with the mild cognitive impairment: A systematic review[END_REF], ranging from 62 to 87 years old. No review integrated older adults with MCR.

Eight reviews assessed cognitive outcomes, including global cognition, memory, attention, executive functions, processing speed, verbal fluency, reaction time, motivation, and orientation [START_REF] Bruderer-Hofstetter | Effective multicomponent interventions in comparison to active control and no interventions on physical capacity, cognitive function and instrumental activities of daily living in elderly people with and without mild impaired cognition -A systematic review and network metaanalysis[END_REF][START_REF] Gheysen | Physical activity to improve cognition in older adults: can physical activity programs enriched with cognitive challenges enhance the effects? A systematic review and metaanalysis[END_REF][START_REF] Karssemeijer | Positive effects of combined cognitive and physical exercise training on cognitive function in older adults with mild cognitive impairment or dementia: A meta-analysis[END_REF][START_REF] Law | Effects of combined cognitive and exercise interventions on cognition in older adults with and without cognitive impairment: A systematic review[END_REF][START_REF] Lipardo | Effect of Exercise and Cognitive Training on Falls and Fall-Related Factors in Older Adults With Mild Cognitive Impairment: A Systematic Review[END_REF][START_REF] Özbe | Immediate Intervention Effects of Standardized Multicomponent Group Interventions on People with Cognitive Impairment: A Systematic Review[END_REF][START_REF] Untari | A combination of cognitive training and physical exercise for elderly with the mild cognitive impairment: A systematic review[END_REF][START_REF] Yang | Effectiveness of Combined Cognitive and Physical Interventions to Enhance Functioning in Older Adults With Mild Cognitive Impairment: A Systematic Review of Randomized Controlled Trials[END_REF]. Brain cortex structure changes were reported in four studies within one review [START_REF] Yang | Effectiveness of Combined Cognitive and Physical Interventions to Enhance Functioning in Older Adults With Mild Cognitive Impairment: A Systematic Review of Randomized Controlled Trials[END_REF], reporting no effects of CMDT on grey matter volume [START_REF] Anderson-Hanley | The Aerobic and Cognitive Exercise Study (ACES) for Community-Dwelling Older Adults With or At-Risk for Mild Cognitive Impairment (MCI): Neuropsychological, Neurobiological and Neuroimaging Outcomes of a Randomized Clinical Trial[END_REF][START_REF] The | Randomized trial on the effects of a combined physical/cognitive training in aged MCI subjects: the Train the Brain study[END_REF], or better results for CMDT than control groups [START_REF] Köbe | Combined omega-3 fatty acids, aerobic exercise and cognitive stimulation prevents decline in gray matter volume of the frontal, parietal and cingulate cortex in patients with mild cognitive impairment[END_REF][START_REF] Shimada | Effects of Combined Physical and Cognitive Exercises on Cognition and Mobility in Patients With Mild Cognitive Impairment: A Randomized Clinical Trial[END_REF]. Four reviews assessed physical outcomes, including gait, balance, strength, mobility, flexibility, falls occurrence and rate, cardiorespiratory fitness, and physical health and activity [START_REF] Booth | Interventions incorporating physical and cognitive elements to reduce falls risk in cognitively impaired older adults: a systematic review[END_REF][START_REF] Bruderer-Hofstetter | Effective multicomponent interventions in comparison to active control and no interventions on physical capacity, cognitive function and instrumental activities of daily living in elderly people with and without mild impaired cognition -A systematic review and network metaanalysis[END_REF][START_REF] Lipardo | Effect of Exercise and Cognitive Training on Falls and Fall-Related Factors in Older Adults With Mild Cognitive Impairment: A Systematic Review[END_REF][START_REF] Yang | Effectiveness of Combined Cognitive and Physical Interventions to Enhance Functioning in Older Adults With Mild Cognitive Impairment: A Systematic Review of Randomized Controlled Trials[END_REF]. No review investigated dual-task functions as outcomes. [START_REF] Law | Effects of combined cognitive and exercise interventions on cognition in older adults with and without cognitive impairment: A systematic review[END_REF][START_REF] Özbe | Immediate Intervention Effects of Standardized Multicomponent Group Interventions on People with Cognitive Impairment: A Systematic Review[END_REF][START_REF] Yang | Effectiveness of Combined Cognitive and Physical Interventions to Enhance Functioning in Older Adults With Mild Cognitive Impairment: A Systematic Review of Randomized Controlled Trials[END_REF], mind-body exercises such as taichi, dance, music or martial arts [START_REF] Booth | Interventions incorporating physical and cognitive elements to reduce falls risk in cognitively impaired older adults: a systematic review[END_REF][START_REF] Bruderer-Hofstetter | Effective multicomponent interventions in comparison to active control and no interventions on physical capacity, cognitive function and instrumental activities of daily living in elderly people with and without mild impaired cognition -A systematic review and network metaanalysis[END_REF][START_REF] Gheysen | Physical activity to improve cognition in older adults: can physical activity programs enriched with cognitive challenges enhance the effects? A systematic review and metaanalysis[END_REF], sometimes computer-assisted activities [START_REF] Karssemeijer | Positive effects of combined cognitive and physical exercise training on cognitive function in older adults with mild cognitive impairment or dementia: A meta-analysis[END_REF][START_REF] Lipardo | Effect of Exercise and Cognitive Training on Falls and Fall-Related Factors in Older Adults With Mild Cognitive Impairment: A Systematic Review[END_REF][START_REF] Untari | A combination of cognitive training and physical exercise for elderly with the mild cognitive impairment: A systematic review[END_REF]. The cognitive and motor tasks were either to be performed simultaneously [START_REF] Booth | Interventions incorporating physical and cognitive elements to reduce falls risk in cognitively impaired older adults: a systematic review[END_REF][START_REF] Untari | A combination of cognitive training and physical exercise for elderly with the mild cognitive impairment: A systematic review[END_REF], or simultaneously and sequentially [START_REF] Bruderer-Hofstetter | Effective multicomponent interventions in comparison to active control and no interventions on physical capacity, cognitive function and instrumental activities of daily living in elderly people with and without mild impaired cognition -A systematic review and network metaanalysis[END_REF][START_REF] Gheysen | Physical activity to improve cognition in older adults: can physical activity programs enriched with cognitive challenges enhance the effects? A systematic review and metaanalysis[END_REF][START_REF] Karssemeijer | Positive effects of combined cognitive and physical exercise training on cognitive function in older adults with mild cognitive impairment or dementia: A meta-analysis[END_REF][START_REF] Law | Effects of combined cognitive and exercise interventions on cognition in older adults with and without cognitive impairment: A systematic review[END_REF][START_REF] Lipardo | Effect of Exercise and Cognitive Training on Falls and Fall-Related Factors in Older Adults With Mild Cognitive Impairment: A Systematic Review[END_REF][START_REF] Özbe | Immediate Intervention Effects of Standardized Multicomponent Group Interventions on People with Cognitive Impairment: A Systematic Review[END_REF][START_REF] Yang | Effectiveness of Combined Cognitive and Physical Interventions to Enhance Functioning in Older Adults With Mild Cognitive Impairment: A Systematic Review of Randomized Controlled Trials[END_REF]. Interventions were mostly distributed in groups rather than individually [START_REF] Booth | Interventions incorporating physical and cognitive elements to reduce falls risk in cognitively impaired older adults: a systematic review[END_REF][START_REF] Bruderer-Hofstetter | Effective multicomponent interventions in comparison to active control and no interventions on physical capacity, cognitive function and instrumental activities of daily living in elderly people with and without mild impaired cognition -A systematic review and network metaanalysis[END_REF][START_REF] Karssemeijer | Positive effects of combined cognitive and physical exercise training on cognitive function in older adults with mild cognitive impairment or dementia: A meta-analysis[END_REF][START_REF] Yang | Effectiveness of Combined Cognitive and Physical Interventions to Enhance Functioning in Older Adults With Mild Cognitive Impairment: A Systematic Review of Randomized Controlled Trials[END_REF], and mixed between home and center-based [START_REF] Bruderer-Hofstetter | Effective multicomponent interventions in comparison to active control and no interventions on physical capacity, cognitive function and instrumental activities of daily living in elderly people with and without mild impaired cognition -A systematic review and network metaanalysis[END_REF][START_REF] Law | Effects of combined cognitive and exercise interventions on cognition in older adults with and without cognitive impairment: A systematic review[END_REF][START_REF] Özbe | Immediate Intervention Effects of Standardized Multicomponent Group Interventions on People with Cognitive Impairment: A Systematic Review[END_REF][START_REF] Yang | Effectiveness of Combined Cognitive and Physical Interventions to Enhance Functioning in Older Adults With Mild Cognitive Impairment: A Systematic Review of Randomized Controlled Trials[END_REF]. Studies that did not take place at home were qualified as centerbased (e.g. in a center, a laboratory, a hospital, a clinic, or in a community association).

CMDT were compared to active control groups (cognitive or motor single-task training or activities, usual care or traditional intervention) or no intervention [START_REF] Booth | Interventions incorporating physical and cognitive elements to reduce falls risk in cognitively impaired older adults: a systematic review[END_REF][START_REF] Bruderer-Hofstetter | Effective multicomponent interventions in comparison to active control and no interventions on physical capacity, cognitive function and instrumental activities of daily living in elderly people with and without mild impaired cognition -A systematic review and network metaanalysis[END_REF][START_REF] Gheysen | Physical activity to improve cognition in older adults: can physical activity programs enriched with cognitive challenges enhance the effects? A systematic review and metaanalysis[END_REF][START_REF] Karssemeijer | Positive effects of combined cognitive and physical exercise training on cognitive function in older adults with mild cognitive impairment or dementia: A meta-analysis[END_REF][START_REF] Law | Effects of combined cognitive and exercise interventions on cognition in older adults with and without cognitive impairment: A systematic review[END_REF][START_REF] Lipardo | Effect of Exercise and Cognitive Training on Falls and Fall-Related Factors in Older Adults With Mild Cognitive Impairment: A Systematic Review[END_REF][START_REF] Özbe | Immediate Intervention Effects of Standardized Multicomponent Group Interventions on People with Cognitive Impairment: A Systematic Review[END_REF][START_REF] Untari | A combination of cognitive training and physical exercise for elderly with the mild cognitive impairment: A systematic review[END_REF][START_REF] Yang | Effectiveness of Combined Cognitive and Physical Interventions to Enhance Functioning in Older Adults With Mild Cognitive Impairment: A Systematic Review of Randomized Controlled Trials[END_REF], including placebo [START_REF] Lipardo | Effect of Exercise and Cognitive Training on Falls and Fall-Related Factors in Older Adults With Mild Cognitive Impairment: A Systematic Review[END_REF][START_REF] Özbe | Immediate Intervention Effects of Standardized Multicomponent Group Interventions on People with Cognitive Impairment: A Systematic Review[END_REF][START_REF] Untari | A combination of cognitive training and physical exercise for elderly with the mild cognitive impairment: A systematic review[END_REF] or education [START_REF] Law | Effects of combined cognitive and exercise interventions on cognition in older adults with and without cognitive impairment: A systematic review[END_REF][START_REF] Lipardo | Effect of Exercise and Cognitive Training on Falls and Fall-Related Factors in Older Adults With Mild Cognitive Impairment: A Systematic Review[END_REF][START_REF] Özbe | Immediate Intervention Effects of Standardized Multicomponent Group Interventions on People with Cognitive Impairment: A Systematic Review[END_REF][START_REF] Untari | A combination of cognitive training and physical exercise for elderly with the mild cognitive impairment: A systematic review[END_REF].

Effectiveness of CMDT interventions

On cognitive functions

CMDT interventions presented mixed effects on cognitive functions in cognitively impaired older adults: they were found effective in three reviews [START_REF] Law | Effects of combined cognitive and exercise interventions on cognition in older adults with and without cognitive impairment: A systematic review[END_REF][START_REF] Lipardo | Effect of Exercise and Cognitive Training on Falls and Fall-Related Factors in Older Adults With Mild Cognitive Impairment: A Systematic Review[END_REF][START_REF] Untari | A combination of cognitive training and physical exercise for elderly with the mild cognitive impairment: A systematic review[END_REF], and ineffective in one other [START_REF] Özbe | Immediate Intervention Effects of Standardized Multicomponent Group Interventions on People with Cognitive Impairment: A Systematic Review[END_REF]. The benefits of CMDT interventions on cognitive functions were clearer when compared with active control groups: CMDT intervention presented superior benefits on cognition than physical [START_REF] Bruderer-Hofstetter | Effective multicomponent interventions in comparison to active control and no interventions on physical capacity, cognitive function and instrumental activities of daily living in elderly people with and without mild impaired cognition -A systematic review and network metaanalysis[END_REF][START_REF] Gheysen | Physical activity to improve cognition in older adults: can physical activity programs enriched with cognitive challenges enhance the effects? A systematic review and metaanalysis[END_REF][START_REF] Karssemeijer | Positive effects of combined cognitive and physical exercise training on cognitive function in older adults with mild cognitive impairment or dementia: A meta-analysis[END_REF][START_REF] Yang | Effectiveness of Combined Cognitive and Physical Interventions to Enhance Functioning in Older Adults With Mild Cognitive Impairment: A Systematic Review of Randomized Controlled Trials[END_REF] and cognitive [START_REF] Bruderer-Hofstetter | Effective multicomponent interventions in comparison to active control and no interventions on physical capacity, cognitive function and instrumental activities of daily living in elderly people with and without mild impaired cognition -A systematic review and network metaanalysis[END_REF][START_REF] Yang | Effectiveness of Combined Cognitive and Physical Interventions to Enhance Functioning in Older Adults With Mild Cognitive Impairment: A Systematic Review of Randomized Controlled Trials[END_REF] training (Figure 2). CMDT interventions seem to be effective on global cognition [START_REF] Bruderer-Hofstetter | Effective multicomponent interventions in comparison to active control and no interventions on physical capacity, cognitive function and instrumental activities of daily living in elderly people with and without mild impaired cognition -A systematic review and network metaanalysis[END_REF][START_REF] Karssemeijer | Positive effects of combined cognitive and physical exercise training on cognitive function in older adults with mild cognitive impairment or dementia: A meta-analysis[END_REF][START_REF] Law | Effects of combined cognitive and exercise interventions on cognition in older adults with and without cognitive impairment: A systematic review[END_REF][START_REF] Lipardo | Effect of Exercise and Cognitive Training on Falls and Fall-Related Factors in Older Adults With Mild Cognitive Impairment: A Systematic Review[END_REF][START_REF] Yang | Effectiveness of Combined Cognitive and Physical Interventions to Enhance Functioning in Older Adults With Mild Cognitive Impairment: A Systematic Review of Randomized Controlled Trials[END_REF], executive functions [START_REF] Karssemeijer | Positive effects of combined cognitive and physical exercise training on cognitive function in older adults with mild cognitive impairment or dementia: A meta-analysis[END_REF][START_REF] Law | Effects of combined cognitive and exercise interventions on cognition in older adults with and without cognitive impairment: A systematic review[END_REF][START_REF] Yang | Effectiveness of Combined Cognitive and Physical Interventions to Enhance Functioning in Older Adults With Mild Cognitive Impairment: A Systematic Review of Randomized Controlled Trials[END_REF] and memory [START_REF] Bruderer-Hofstetter | Effective multicomponent interventions in comparison to active control and no interventions on physical capacity, cognitive function and instrumental activities of daily living in elderly people with and without mild impaired cognition -A systematic review and network metaanalysis[END_REF][START_REF] Karssemeijer | Positive effects of combined cognitive and physical exercise training on cognitive function in older adults with mild cognitive impairment or dementia: A meta-analysis[END_REF][START_REF] Law | Effects of combined cognitive and exercise interventions on cognition in older adults with and without cognitive impairment: A systematic review[END_REF][START_REF] Lipardo | Effect of Exercise and Cognitive Training on Falls and Fall-Related Factors in Older Adults With Mild Cognitive Impairment: A Systematic Review[END_REF][START_REF] Yang | Effectiveness of Combined Cognitive and Physical Interventions to Enhance Functioning in Older Adults With Mild Cognitive Impairment: A Systematic Review of Randomized Controlled Trials[END_REF].

On physical functions

CMDT interventions have been found effective in improving physical function in older adults

with MCI or dementias [START_REF] Lipardo | Effect of Exercise and Cognitive Training on Falls and Fall-Related Factors in Older Adults With Mild Cognitive Impairment: A Systematic Review[END_REF]. This was confirmed when compared to active control groups:

CMDT intervention presented superior benefits on physical function than physical [START_REF] Booth | Interventions incorporating physical and cognitive elements to reduce falls risk in cognitively impaired older adults: a systematic review[END_REF][START_REF] Bruderer-Hofstetter | Effective multicomponent interventions in comparison to active control and no interventions on physical capacity, cognitive function and instrumental activities of daily living in elderly people with and without mild impaired cognition -A systematic review and network metaanalysis[END_REF][START_REF] Yang | Effectiveness of Combined Cognitive and Physical Interventions to Enhance Functioning in Older Adults With Mild Cognitive Impairment: A Systematic Review of Randomized Controlled Trials[END_REF] and cognitive [START_REF] Bruderer-Hofstetter | Effective multicomponent interventions in comparison to active control and no interventions on physical capacity, cognitive function and instrumental activities of daily living in elderly people with and without mild impaired cognition -A systematic review and network metaanalysis[END_REF][START_REF] Yang | Effectiveness of Combined Cognitive and Physical Interventions to Enhance Functioning in Older Adults With Mild Cognitive Impairment: A Systematic Review of Randomized Controlled Trials[END_REF] training alone (Figure 2). More specifically, CMDT interventions seem to be effective on balance [START_REF] Booth | Interventions incorporating physical and cognitive elements to reduce falls risk in cognitively impaired older adults: a systematic review[END_REF][START_REF] Bruderer-Hofstetter | Effective multicomponent interventions in comparison to active control and no interventions on physical capacity, cognitive function and instrumental activities of daily living in elderly people with and without mild impaired cognition -A systematic review and network metaanalysis[END_REF][START_REF] Lipardo | Effect of Exercise and Cognitive Training on Falls and Fall-Related Factors in Older Adults With Mild Cognitive Impairment: A Systematic Review[END_REF][START_REF] Yang | Effectiveness of Combined Cognitive and Physical Interventions to Enhance Functioning in Older Adults With Mild Cognitive Impairment: A Systematic Review of Randomized Controlled Trials[END_REF], mobility [START_REF] Booth | Interventions incorporating physical and cognitive elements to reduce falls risk in cognitively impaired older adults: a systematic review[END_REF][START_REF] Yang | Effectiveness of Combined Cognitive and Physical Interventions to Enhance Functioning in Older Adults With Mild Cognitive Impairment: A Systematic Review of Randomized Controlled Trials[END_REF], gait [START_REF] Booth | Interventions incorporating physical and cognitive elements to reduce falls risk in cognitively impaired older adults: a systematic review[END_REF][START_REF] Yang | Effectiveness of Combined Cognitive and Physical Interventions to Enhance Functioning in Older Adults With Mild Cognitive Impairment: A Systematic Review of Randomized Controlled Trials[END_REF], strength [START_REF] Bruderer-Hofstetter | Effective multicomponent interventions in comparison to active control and no interventions on physical capacity, cognitive function and instrumental activities of daily living in elderly people with and without mild impaired cognition -A systematic review and network metaanalysis[END_REF],

physical activity [START_REF] Yang | Effectiveness of Combined Cognitive and Physical Interventions to Enhance Functioning in Older Adults With Mild Cognitive Impairment: A Systematic Review of Randomized Controlled Trials[END_REF] and cardiorespiratory fitness [START_REF] Bruderer-Hofstetter | Effective multicomponent interventions in comparison to active control and no interventions on physical capacity, cognitive function and instrumental activities of daily living in elderly people with and without mild impaired cognition -A systematic review and network metaanalysis[END_REF][START_REF] Yang | Effectiveness of Combined Cognitive and Physical Interventions to Enhance Functioning in Older Adults With Mild Cognitive Impairment: A Systematic Review of Randomized Controlled Trials[END_REF].

Supervision, safety, adherence, and retention of benefits

Degree of supervision was reported in three reviews [START_REF] Bruderer-Hofstetter | Effective multicomponent interventions in comparison to active control and no interventions on physical capacity, cognitive function and instrumental activities of daily living in elderly people with and without mild impaired cognition -A systematic review and network metaanalysis[END_REF][START_REF] Law | Effects of combined cognitive and exercise interventions on cognition in older adults with and without cognitive impairment: A systematic review[END_REF][START_REF] Yang | Effectiveness of Combined Cognitive and Physical Interventions to Enhance Functioning in Older Adults With Mild Cognitive Impairment: A Systematic Review of Randomized Controlled Trials[END_REF]; CMDT interventions in older adults with MCI or dementias were mostly supervised [START_REF] Law | Effects of combined cognitive and exercise interventions on cognition in older adults with and without cognitive impairment: A systematic review[END_REF][START_REF] Yang | Effectiveness of Combined Cognitive and Physical Interventions to Enhance Functioning in Older Adults With Mild Cognitive Impairment: A Systematic Review of Randomized Controlled Trials[END_REF] or unsupervised [START_REF] Bruderer-Hofstetter | Effective multicomponent interventions in comparison to active control and no interventions on physical capacity, cognitive function and instrumental activities of daily living in elderly people with and without mild impaired cognition -A systematic review and network metaanalysis[END_REF].

One review assessed interventions' safety [START_REF] Özbe | Immediate Intervention Effects of Standardized Multicomponent Group Interventions on People with Cognitive Impairment: A Systematic Review[END_REF] and reported no difference in the occurrence of adverse events between intervention and control groups. One other review assessed adherence and reported a low average drop-out rate [START_REF] Yang | Effectiveness of Combined Cognitive and Physical Interventions to Enhance Functioning in Older Adults With Mild Cognitive Impairment: A Systematic Review of Randomized Controlled Trials[END_REF]. Finally, only one study [START_REF] Oswald | Differential effects of single versus combined cognitive and physical training with older adults: the SimA study in a 5-year perspective[END_REF] included in one review [START_REF] Law | Effects of combined cognitive and exercise interventions on cognition in older adults with and without cognitive impairment: A systematic review[END_REF] reported 5-year retention of benefits. Across reviews, authors agree on the need for investigation of long-term effects [START_REF] Gheysen | Physical activity to improve cognition in older adults: can physical activity programs enriched with cognitive challenges enhance the effects? A systematic review and metaanalysis[END_REF][START_REF] Karssemeijer | Positive effects of combined cognitive and physical exercise training on cognitive function in older adults with mild cognitive impairment or dementia: A meta-analysis[END_REF][START_REF] Özbe | Immediate Intervention Effects of Standardized Multicomponent Group Interventions on People with Cognitive Impairment: A Systematic Review[END_REF][START_REF] Untari | A combination of cognitive training and physical exercise for elderly with the mild cognitive impairment: A systematic review[END_REF].

Methodological quality, risk of bias, quality of evidence and funding

Details of the AMSTAR-2 assessment of methodological quality are presented in Table 2.

Two authors (MGG and AP) agreed at 90% in their rating across the nine systematic reviews included. The overall quality was critically low in seven reviews [START_REF] Bruderer-Hofstetter | Effective multicomponent interventions in comparison to active control and no interventions on physical capacity, cognitive function and instrumental activities of daily living in elderly people with and without mild impaired cognition -A systematic review and network metaanalysis[END_REF][START_REF] Gheysen | Physical activity to improve cognition in older adults: can physical activity programs enriched with cognitive challenges enhance the effects? A systematic review and metaanalysis[END_REF][START_REF] Karssemeijer | Positive effects of combined cognitive and physical exercise training on cognitive function in older adults with mild cognitive impairment or dementia: A meta-analysis[END_REF][START_REF] Law | Effects of combined cognitive and exercise interventions on cognition in older adults with and without cognitive impairment: A systematic review[END_REF][START_REF] Özbe | Immediate Intervention Effects of Standardized Multicomponent Group Interventions on People with Cognitive Impairment: A Systematic Review[END_REF][START_REF] Untari | A combination of cognitive training and physical exercise for elderly with the mild cognitive impairment: A systematic review[END_REF][START_REF] Yang | Effectiveness of Combined Cognitive and Physical Interventions to Enhance Functioning in Older Adults With Mild Cognitive Impairment: A Systematic Review of Randomized Controlled Trials[END_REF], and low in two [START_REF] Booth | Interventions incorporating physical and cognitive elements to reduce falls risk in cognitively impaired older adults: a systematic review[END_REF][START_REF] Lipardo | Effect of Exercise and Cognitive Training on Falls and Fall-Related Factors in Older Adults With Mild Cognitive Impairment: A Systematic Review[END_REF], with a 7/16 mean score.

Table 2: Methodological quality of the reviews included

Discussion

Effects of CMDT trainings

This overview aimed at summarizing the effects of CMDT training on cognitive, physical and dual-task functions in cognitively impaired older adults. Overall, this type of intervention seems to be effective on both cognitive and physical functions in adults with MCI or dementias, with superior effects compared to active and inactive control groups. However, this overview also highlighted understudied elements, such as effects on dual-task functions, modalities, optimal dose and retention of benefits of interventions.

Cognitive functions

CMDT interventions showed positive effects in older adults with MCI or dementias in different domains: global cognition [START_REF] Bruderer-Hofstetter | Effective multicomponent interventions in comparison to active control and no interventions on physical capacity, cognitive function and instrumental activities of daily living in elderly people with and without mild impaired cognition -A systematic review and network metaanalysis[END_REF][START_REF] Karssemeijer | Positive effects of combined cognitive and physical exercise training on cognitive function in older adults with mild cognitive impairment or dementia: A meta-analysis[END_REF][START_REF] Law | Effects of combined cognitive and exercise interventions on cognition in older adults with and without cognitive impairment: A systematic review[END_REF][START_REF] Lipardo | Effect of Exercise and Cognitive Training on Falls and Fall-Related Factors in Older Adults With Mild Cognitive Impairment: A Systematic Review[END_REF][START_REF] Yang | Effectiveness of Combined Cognitive and Physical Interventions to Enhance Functioning in Older Adults With Mild Cognitive Impairment: A Systematic Review of Randomized Controlled Trials[END_REF], executive functions [START_REF] Karssemeijer | Positive effects of combined cognitive and physical exercise training on cognitive function in older adults with mild cognitive impairment or dementia: A meta-analysis[END_REF][START_REF] Law | Effects of combined cognitive and exercise interventions on cognition in older adults with and without cognitive impairment: A systematic review[END_REF][START_REF] Yang | Effectiveness of Combined Cognitive and Physical Interventions to Enhance Functioning in Older Adults With Mild Cognitive Impairment: A Systematic Review of Randomized Controlled Trials[END_REF] and memory [START_REF] Bruderer-Hofstetter | Effective multicomponent interventions in comparison to active control and no interventions on physical capacity, cognitive function and instrumental activities of daily living in elderly people with and without mild impaired cognition -A systematic review and network metaanalysis[END_REF][START_REF] Karssemeijer | Positive effects of combined cognitive and physical exercise training on cognitive function in older adults with mild cognitive impairment or dementia: A meta-analysis[END_REF][START_REF] Law | Effects of combined cognitive and exercise interventions on cognition in older adults with and without cognitive impairment: A systematic review[END_REF][START_REF] Lipardo | Effect of Exercise and Cognitive Training on Falls and Fall-Related Factors in Older Adults With Mild Cognitive Impairment: A Systematic Review[END_REF][START_REF] Yang | Effectiveness of Combined Cognitive and Physical Interventions to Enhance Functioning in Older Adults With Mild Cognitive Impairment: A Systematic Review of Randomized Controlled Trials[END_REF]]. There appears to be no effect of cognitive domain on efficacy [START_REF] Karssemeijer | Positive effects of combined cognitive and physical exercise training on cognitive function in older adults with mild cognitive impairment or dementia: A meta-analysis[END_REF]. It is worth noting that one review found no effects of CMDT on global cognition or memory [START_REF] Özbe | Immediate Intervention Effects of Standardized Multicomponent Group Interventions on People with Cognitive Impairment: A Systematic Review[END_REF]. However, it is difficult to know what cognitive and physical components of interventions are included in this review. Furthermore, this review from Özbe et al. found positive effects of CMDT on dual-task performance, even though it is not part of the described outcomes. We therefore preferred to retain the conclusion common to all of the other authors.

Motor functions

CMDT interventions showed positive effects in cognitively impaired older adults specifically on balance [START_REF] Booth | Falls prevention interventions in older adults with cognitive impairment: A systematic review of reviews[END_REF][START_REF] Bruderer-Hofstetter | Effective multicomponent interventions in comparison to active control and no interventions on physical capacity, cognitive function and instrumental activities of daily living in elderly people with and without mild impaired cognition -A systematic review and network metaanalysis[END_REF][START_REF] Lipardo | Effect of Exercise and Cognitive Training on Falls and Fall-Related Factors in Older Adults With Mild Cognitive Impairment: A Systematic Review[END_REF][START_REF] Yang | Effectiveness of Combined Cognitive and Physical Interventions to Enhance Functioning in Older Adults With Mild Cognitive Impairment: A Systematic Review of Randomized Controlled Trials[END_REF], mobility [START_REF] Booth | Falls prevention interventions in older adults with cognitive impairment: A systematic review of reviews[END_REF][START_REF] Yang | Effectiveness of Combined Cognitive and Physical Interventions to Enhance Functioning in Older Adults With Mild Cognitive Impairment: A Systematic Review of Randomized Controlled Trials[END_REF], gait [START_REF] Booth | Falls prevention interventions in older adults with cognitive impairment: A systematic review of reviews[END_REF][START_REF] Yang | Effectiveness of Combined Cognitive and Physical Interventions to Enhance Functioning in Older Adults With Mild Cognitive Impairment: A Systematic Review of Randomized Controlled Trials[END_REF], strength [START_REF] Bruderer-Hofstetter | Effective multicomponent interventions in comparison to active control and no interventions on physical capacity, cognitive function and instrumental activities of daily living in elderly people with and without mild impaired cognition -A systematic review and network metaanalysis[END_REF], physical activity [START_REF] Yang | Effectiveness of Combined Cognitive and Physical Interventions to Enhance Functioning in Older Adults With Mild Cognitive Impairment: A Systematic Review of Randomized Controlled Trials[END_REF] and cardiorespiratory fitness [START_REF] Bruderer-Hofstetter | Effective multicomponent interventions in comparison to active control and no interventions on physical capacity, cognitive function and instrumental activities of daily living in elderly people with and without mild impaired cognition -A systematic review and network metaanalysis[END_REF][START_REF] Yang | Effectiveness of Combined Cognitive and Physical Interventions to Enhance Functioning in Older Adults With Mild Cognitive Impairment: A Systematic Review of Randomized Controlled Trials[END_REF]. Even though the loss in balance, mobility, gait and strength are known to be risk factors for falls, the effects of CMDT interventions on falls occurrence in cognitively impaired adults remains unclear [START_REF] Booth | Falls prevention interventions in older adults with cognitive impairment: A systematic review of reviews[END_REF].

Moderator parameters

Participants' status

Two meta-analyses evaluated the effects of CMDT interventions according to participants' cognitive status [START_REF] Gheysen | Physical activity to improve cognition in older adults: can physical activity programs enriched with cognitive challenges enhance the effects? A systematic review and metaanalysis[END_REF][START_REF] Karssemeijer | Positive effects of combined cognitive and physical exercise training on cognitive function in older adults with mild cognitive impairment or dementia: A meta-analysis[END_REF]. The effects were found to be equivalent between healthy and MCI older adults [START_REF] Gheysen | Physical activity to improve cognition in older adults: can physical activity programs enriched with cognitive challenges enhance the effects? A systematic review and metaanalysis[END_REF], but differences between older adults with MCI or dementia was unclear [START_REF] Karssemeijer | Positive effects of combined cognitive and physical exercise training on cognitive function in older adults with mild cognitive impairment or dementia: A meta-analysis[END_REF]. It seems logical that severity of participants' cognitive impairment would have an impact on the intervention benefits, but this does not yet seem to be confirmed. In addition, no review assessed the impact of participants' physical status.

Intervention modalities

The optimal dose is difficult to define: meta-analysis showed that CMDT intervention length, duration or frequency had no impact on their efficiency [START_REF] Bruderer-Hofstetter | Effective multicomponent interventions in comparison to active control and no interventions on physical capacity, cognitive function and instrumental activities of daily living in elderly people with and without mild impaired cognition -A systematic review and network metaanalysis[END_REF][START_REF] Gheysen | Physical activity to improve cognition in older adults: can physical activity programs enriched with cognitive challenges enhance the effects? A systematic review and metaanalysis[END_REF]. In addition, these interventions were effective in improving cognitive and physical functions even at short doses of four weeks [START_REF] Bruderer-Hofstetter | Effective multicomponent interventions in comparison to active control and no interventions on physical capacity, cognitive function and instrumental activities of daily living in elderly people with and without mild impaired cognition -A systematic review and network metaanalysis[END_REF]. A previous meta-analysis even found a negative association between the intervention length and the effects on cognition in adults with MCI [START_REF] Li | Cognitive intervention for persons with mild cognitive impairment: A meta-analysis[END_REF]. This might be explained by a cognitive fatigue [START_REF] Lampit | Computerized Cognitive Training in Cognitively Healthy Older Adults: A Systematic Review and Meta-Analysis of Effect Modifiers Gandy S[END_REF] or excessive stress [START_REF] Singh | The Study of Mental and Resistance Training (SMART) Study-Resistance Training and/or Cognitive Training in Mild Cognitive Impairment: A Randomized, Double-Blind, Double-Sham Controlled Trial[END_REF] due to combined mental and physical exertion.

CMDT interventions were mostly group-based, which seems to be recommended for better benefits on cognitive and physical functions [START_REF] Bruderer-Hofstetter | Effective multicomponent interventions in comparison to active control and no interventions on physical capacity, cognitive function and instrumental activities of daily living in elderly people with and without mild impaired cognition -A systematic review and network metaanalysis[END_REF], although it seems that an individualized approach could have greater effects on fall rates in older adults with cognitive impairment compared with a group exercise [START_REF] Booth | Interventions incorporating physical and cognitive elements to reduce falls risk in cognitively impaired older adults: a systematic review[END_REF]. In order to maximize the transfer effect, functional exercises should be the main focus [START_REF] Bruderer-Hofstetter | Effective multicomponent interventions in comparison to active control and no interventions on physical capacity, cognitive function and instrumental activities of daily living in elderly people with and without mild impaired cognition -A systematic review and network metaanalysis[END_REF]. Although the majority of interventions consisted of simultaneous CMDT, it is unclear whether the two tasks should be performed simultaneously or sequentially. Some authors found simultaneous CMDT more effective than sequential cognitive-motor trainings for adults with MCI [START_REF] Gheysen | Physical activity to improve cognition in older adults: can physical activity programs enriched with cognitive challenges enhance the effects? A systematic review and metaanalysis[END_REF], while others found the opposite [START_REF] Bruderer-Hofstetter | Effective multicomponent interventions in comparison to active control and no interventions on physical capacity, cognitive function and instrumental activities of daily living in elderly people with and without mild impaired cognition -A systematic review and network metaanalysis[END_REF]. This has already been explored in cognitively healthy adults, and the advantage on cognitive improvement for simultaneous CMDT [START_REF] Tait | Influence of Sequential vs. Simultaneous Dual-Task Exercise Training on Cognitive Function in Older Adults[END_REF] may be due to the increased brain-delivered neurotrophic factor (BDNF) after physical activity [START_REF] Knaepen | Neuroplasticity -Exercise-Induced Response of Peripheral Brain-Derived Neurotrophic Factor: A Systematic Review of Experimental Studies in Human Subjects[END_REF].

Feasibility

Although supervision does not appear to be essential [START_REF] Bruderer-Hofstetter | Effective multicomponent interventions in comparison to active control and no interventions on physical capacity, cognitive function and instrumental activities of daily living in elderly people with and without mild impaired cognition -A systematic review and network metaanalysis[END_REF], and safety [START_REF] Özbe | Immediate Intervention Effects of Standardized Multicomponent Group Interventions on People with Cognitive Impairment: A Systematic Review[END_REF], adherence [START_REF] Yang | Effectiveness of Combined Cognitive and Physical Interventions to Enhance Functioning in Older Adults With Mild Cognitive Impairment: A Systematic Review of Randomized Controlled Trials[END_REF] and retention [START_REF] Law | Effects of combined cognitive and exercise interventions on cognition in older adults with and without cognitive impairment: A systematic review[END_REF] were good when reported, these data were almost never reported in reviews, and were overall understudied in included studies within reviews. However, this is very important information, because presence of MCI or dementia requires long-term adhesion to the training program and the ability to practice this alone safely. It is also important to discuss what adequate "retention" is implied in this population. Indeed, the evolutionary aspect of cognitive impairment such as MCI or dementias implies that maintaining performance is an ideal objective, and that slowing down the degradation would in itself be beneficial.

Quality and risk of bias

This overview presents an average low methodological quality and high risk of bias of the included reviews. The AMSTAR-2 tool we used showed an overall critically low confidence in the results of the included reviews, even though seven of them followed PRISMA or Cochrane Guidelines [START_REF] Booth | Interventions incorporating physical and cognitive elements to reduce falls risk in cognitively impaired older adults: a systematic review[END_REF][START_REF] Bruderer-Hofstetter | Effective multicomponent interventions in comparison to active control and no interventions on physical capacity, cognitive function and instrumental activities of daily living in elderly people with and without mild impaired cognition -A systematic review and network metaanalysis[END_REF][START_REF] Gheysen | Physical activity to improve cognition in older adults: can physical activity programs enriched with cognitive challenges enhance the effects? A systematic review and metaanalysis[END_REF][START_REF] Karssemeijer | Positive effects of combined cognitive and physical exercise training on cognitive function in older adults with mild cognitive impairment or dementia: A meta-analysis[END_REF][START_REF] Law | Effects of combined cognitive and exercise interventions on cognition in older adults with and without cognitive impairment: A systematic review[END_REF][START_REF] Untari | A combination of cognitive training and physical exercise for elderly with the mild cognitive impairment: A systematic review[END_REF][START_REF] Yang | Effectiveness of Combined Cognitive and Physical Interventions to Enhance Functioning in Older Adults With Mild Cognitive Impairment: A Systematic Review of Randomized Controlled Trials[END_REF]. A possible explanation is the critical domains system of the AMSTAR-2 tool. For instance, the 7 th item ("providing the list of excluded studies") was reported as "No" in 7 reviews, dropping their assessment to at least "low" (see

Table 2).

A second limit of this study is inherent to overviews and is due to the great heterogeneity of included reviews. We included here studies of various cognitive impairments (MCI, dementias, AD), program content and modalities, and outcomes (motor and cognitive). All of this can represent a potential source of misinterpretation when generalizing and extrapolating the results. For instance, we observed an overall superior efficiency for CMDT interventions than control groups, mixing comparison to active or inactive groups. It would be interesting to determine whether CMDT interventions are more effective than placebo, an education program, or a single-task training program. Also, a distinction between three kinds of "multicomponent interventions" would thus be relevant for better readability [START_REF] Anderson-Hanley | The Aerobic and Cognitive Exercise Study (ACES) for Community-Dwelling Older Adults With or At-Risk for Mild Cognitive Impairment (MCI): Neuropsychological, Neurobiological and Neuroimaging Outcomes of a Randomized Clinical Trial[END_REF]. Therefore, we could use "combined intervention" for sequential cognitive-motor training, "dual-task intervention" for simultaneous yet distinct tasks (e.g., not functional), and "interactive intervention" in which the actions in one realm affect the other, such as exergames. At last, it is yet unclear if physical and cognitive activities used as control groups in several studies are single task trainings, because they may be multicomponent and include motor-motor or cognitive-cognitive dual-tasks.

Future studies

The positive effects of CMDT interventions on cognitive and physical functions in adults with MCI or dementia no longer require to be proven, and the great heterogeneity in the intervention methodology does not seem to have an impact on efficiency. Conversely, certain elements need to be clarified.

No review included older adults with MCR, who typically show a dual-decline profile of both motor and cognitive functions [START_REF] Verghese | Motoric Cognitive Risk Syndrome and the Risk of Dementia[END_REF]. To our knowledge, there are not yet any trials including adults with MCR, only incidence or prevalence studies. Future studies should assess the effectiveness of CMDT in this population on cognitive, motor and dual-task functions, depending on the subtype and cognitive profile [START_REF] Allali | Motoric Cognitive Risk Syndrome Subtypes and Cognitive Profiles[END_REF]. This is particularly relevant given the increased risk of conversion to dementia in dual-decliners [START_REF] Montero-Odasso | Dual decline in gait speed and cognition is associated with future dementia: evidence for a phenotype[END_REF], and because older adults with MCR are close to MCI with slower gait speed [START_REF] Verghese | Motoric Cognitive Risk Syndrome and the Risk of Dementia[END_REF]. The need to differentiate older adults with MCI according to physical status and functional impairment has already been highlighted [START_REF] Del | Problems in Classifying Mild Cognitive Impairment (MCI): One or Multiple Syndromes?[END_REF]. Future studies should assess the differences between fallers and non-fallers, or between participants with and without gait disorders; it is likely that the consequences of CMDT interventions will be different depending on the severity of motor impairment [START_REF] Del | Problems in Classifying Mild Cognitive Impairment (MCI): One or Multiple Syndromes?[END_REF]. Finally, reviews including participants with dementia did not provide information about the types of dementia [START_REF] Booth | Interventions incorporating physical and cognitive elements to reduce falls risk in cognitively impaired older adults: a systematic review[END_REF][START_REF] Karssemeijer | Positive effects of combined cognitive and physical exercise training on cognitive function in older adults with mild cognitive impairment or dementia: A meta-analysis[END_REF][START_REF] Law | Effects of combined cognitive and exercise interventions on cognition in older adults with and without cognitive impairment: A systematic review[END_REF]. This information would be relevant, because the type of dementia implies different predominant cognitive impairment: disorientation in dementia with Lewy bodies, executive functions in frontotemporal dementia and coordination in AD. Thus, future studies should distinguish participants according to dementia type, because the training content and objective may differ. Some of the included reviews integrated mind-body exercises [START_REF] Booth | Interventions incorporating physical and cognitive elements to reduce falls risk in cognitively impaired older adults: a systematic review[END_REF][START_REF] Bruderer-Hofstetter | Effective multicomponent interventions in comparison to active control and no interventions on physical capacity, cognitive function and instrumental activities of daily living in elderly people with and without mild impaired cognition -A systematic review and network metaanalysis[END_REF][START_REF] Gheysen | Physical activity to improve cognition in older adults: can physical activity programs enriched with cognitive challenges enhance the effects? A systematic review and metaanalysis[END_REF] or exergames [START_REF] Bruderer-Hofstetter | Effective multicomponent interventions in comparison to active control and no interventions on physical capacity, cognitive function and instrumental activities of daily living in elderly people with and without mild impaired cognition -A systematic review and network metaanalysis[END_REF][START_REF] Gheysen | Physical activity to improve cognition in older adults: can physical activity programs enriched with cognitive challenges enhance the effects? A systematic review and metaanalysis[END_REF][START_REF] Karssemeijer | Positive effects of combined cognitive and physical exercise training on cognitive function in older adults with mild cognitive impairment or dementia: A meta-analysis[END_REF]. Future studies should focus on other forms of CMDT than the analytical combination of a motor and a cognitive task, such as music therapy or tai-chi, which may well be more entertaining and encouraging for participants. Exergames, for instance, seem promising [START_REF] Howes | Gaming for Health: Systematic Review and Meta-analysis of the Physical and Cognitive Effects of Active Computer Gaming in Older Adults[END_REF][START_REF] Kim | The effectiveness of virtual reality for people with mild cognitive impairment or dementia: a meta-analysis[END_REF][START_REF] Sultana | Effect of Wii Fit© Exercise on Balance of Older Adults with Neurocognitive Disorders: A Meta-Analysis[END_REF]. Although interventions have been found effective no matter their length, duration and frequency, future studies should evaluate the optimal dose response according to participant characteristics and intervention modalities.

It is surprising that interventions using CMDT as training did not assess the impact on dualtask functions. This was also observed for reviews in cognitively healthy elderly people [START_REF] Gallou-Guyot | Effects of exergames and cognitive-motor dual-task training on cognitive, physical and dual-task functions in cognitively healthy older adults: an overview[END_REF].

We can even consider that measuring the impact of CMDT using single-task evaluations as outcomes does not assess their effectiveness, but the transfer of benefits to other functions. This may be due to the lack of standardized functional assessment for CMDT [START_REF] Agmon | A systematic review of interventions conducted in clinical or community settings to improve dual-task postural control in older adults[END_REF][START_REF] Plummer | Effects of Physical Exercise Interventions on Gait-Related Dual-Task Interference in Older Adults: A Systematic Review and Meta-Analysis[END_REF][START_REF] Wollesen | Influence of a visual-verbal Stroop test on standing and walking performance of older adults[END_REF].

However, dual-tasks are already used as specific screening tools for the management of gait disorders and falls in older adults with MCI or dementia [START_REF] Allali | Management of Gait Changes and Fall Risk in MCI and Dementia[END_REF]. The development of such standardized tools is to be encouraged. Beyond efficiency, future studies should also assess retention of benefits, safety, need for supervision and adherence. The retention of benefits should be evaluated by considering the natural history of degradation of functions in MCI, MCR, dementias or AD, and by considering that a slowdown in this degradation would consist in a retention.

Previous studies in cognitively healthy older adults identified BDNF as a biomarker linking cognitive functions and healthy aging [START_REF] Erickson | The Aging Hippocampus: Interactions between Exercise, Depression, and BDNF[END_REF][START_REF] Maass | Relationships of peripheral IGF-1, VEGF and BDNF levels to exercise-related changes in memory, hippocampal perfusion and volumes in older adults[END_REF]. Moreover, physical activity has been found effective at increasing BDNF secretion [START_REF] Coelho Fg De | Physical exercise modulates peripheral levels of brain-derived neurotrophic factor (BDNF): A systematic review of experimental studies in the elderly[END_REF][START_REF] Knaepen | Neuroplasticity -Exercise-Induced Response of Peripheral Brain-Derived Neurotrophic Factor: A Systematic Review of Experimental Studies in Human Subjects[END_REF][START_REF] Maass | Relationships of peripheral IGF-1, VEGF and BDNF levels to exercise-related changes in memory, hippocampal perfusion and volumes in older adults[END_REF], and CMDT to be as effective as physical activity alone in healthy young subjects [START_REF] Miyamoto | Response of brain-derived neurotrophic factor to combining cognitive and physical exercise[END_REF]. Thus, the impact of CMDT interventions on neuroplasticity facilitation (i.e., increasing BDNF) remains to be explored in cognitively impaired adults, who are known to have lower BDNF serum levels [START_REF] Siuda | Cognitive impairment and BDNF serum levels[END_REF]. An increase in BDNF induces an increase in gray matter volume [START_REF] Colcombe | Aerobic Exercise Training Increases Brain Volume in Aging Humans[END_REF]; this may explain the increase in grey matter observed in few studies [START_REF] Köbe | Combined omega-3 fatty acids, aerobic exercise and cognitive stimulation prevents decline in gray matter volume of the frontal, parietal and cingulate cortex in patients with mild cognitive impairment[END_REF][START_REF] Shimada | Effects of Combined Physical and Cognitive Exercises on Cognition and Mobility in Patients With Mild Cognitive Impairment: A Randomized Clinical Trial[END_REF]. These brain structural modifications are still under debate [START_REF] Anderson-Hanley | The Aerobic and Cognitive Exercise Study (ACES) for Community-Dwelling Older Adults With or At-Risk for Mild Cognitive Impairment (MCI): Neuropsychological, Neurobiological and Neuroimaging Outcomes of a Randomized Clinical Trial[END_REF][START_REF] Köbe | Combined omega-3 fatty acids, aerobic exercise and cognitive stimulation prevents decline in gray matter volume of the frontal, parietal and cingulate cortex in patients with mild cognitive impairment[END_REF][START_REF] Shimada | Effects of Combined Physical and Cognitive Exercises on Cognition and Mobility in Patients With Mild Cognitive Impairment: A Randomized Clinical Trial[END_REF][START_REF] The | Randomized trial on the effects of a combined physical/cognitive training in aged MCI subjects: the Train the Brain study[END_REF], and should be explored in future studies because they represent a potential means of action against the progressive loss of grey matter observed in older adults with MCI [START_REF] Saykin | Older adults with cognitive complaints show brain atrophy similar to that of amnestic MCI[END_REF][START_REF] Wang | Altered default mode network connectivity in older adults with cognitive complaints and amnestic mild cognitive impairment[END_REF] or AD [START_REF] Whitwell | MRI patterns of atrophy associated with progression to AD in amnestic mild cognitive impairment[END_REF].

Conclusion

This overview found positive effects of CMDT interventions on cognitive and physical functions in adults with cognitive impairment, irrespective of intervention dose and modalities. These results should be interpreted carefully, considering their critically low average methodological quality. Future individual research should follow more rigorous methodological standards, and focus on different CMDT training modalities, assessing the optimal dose response. Long-term retention of benefits, need for supervision, and adherence to these interventions also remain to be determined.

n.r. n.r. HE [START_REF] Li | Cognitive intervention for persons with mild cognitive impairment: A meta-analysis[END_REF], MCI

Exp : CMDT ( 12), EG (6), CMDT-EG (1), Tai-chi-Dance-Martial Arts (13), unclear

CG : NI [START_REF] Li | Cognitive intervention for persons with mild cognitive impairment: A meta-analysis[END_REF], PA [START_REF] Howes | Gaming for Health: Systematic Review and Meta-analysis of the Physical and Cognitive Effects of Active Computer Gaming in Older Adults[END_REF], CA ( 10)

Sim (29), seq (9)
1) Effects of CMDT on cognitive functions, ADL and mood SR-MA ( 10) RCT ( 10)

742 (391 / 351) [71 -86] MCI (3), Dem (5), MCI & dem (2)
Exp: CMDT (10), computer assisted Rating overall confidence in the results of the review:

High: no or one non-critical weakness. The systematic review provides an accurate and comprehensive summary of the results of the available studies that address the question of interest

Figure 2 :

 2 Figure 2: Summary of findings

Table 1 :

 1 Characteristics of the reviews included

	Program characteristics were very heterogeneous with respect to frequency (1-6 times a
	week), length (30-180 minutes) and duration (4-52 weeks long). CMDT interventions'
	support varied: gymnastic group-based sessions

Table 1 :

 1 characteristics of included reviews

	Review	Objectives	Included lit.	Population	Interventions	Modalities	Outcome	Conclusions	Specific results	RoB
	First author, year	1) Primary	Reviews design (N)	N (Exp / Ctrl)	Experimental or control group, content	Sim / seq	Types, functions assessed	Effectiveness,	Specific to CI (MCI, Dem	Scale, score or
	Country	2) Secondary	Primary studies	Age (mean	(N)	Ind / grp		comparison	or AD), or secondary	criteria
			design (N)	range)		Center / home		(primary objective)	objective	Mean, range or
				Cognitive		Duration min-				appreciation
				status (N)		max
	Cognitive Outcome
	Gheysen, 2018	1) Effects of	SR (41) -MA (40)
	Belgium	CMDT compared	RCT (32), NRSI
	[20]	to PA and CA
		2) Dose and
		modalities response
		(frequency,
		duration, total
		length, sim/seq)
		3) Preventive
		effects of CMDT

  52w

	Özbe, 2019 Bruderer-	1) Effects of 1) Effects of	SR (9) SR-MA (17)	513 (258 / 255) 1758 (n.r.)	Exp: cognitive (n.r.) + physical Exp: cognitive (memory, executive	Sim (2), seq (7) Sim (9), seq (8)	Cognitive: global cognition, Cognitive: global cognition,	No effects on CMDT effective on	CMDT seem to have no CMDT are more effective	CCRT CCRT
	Germany Hofstetter, 2018	CMDT CMDT on physical	RCT (9) RCT (17)	[70 -85] [66-82]	(resistance, balance, strength, aerobic, function, attention, processing speed,	n.r. Ind (6), grp (12)	memory, flexibility, attention learning and memory, EF,	cognition physical and	global effect on cognition on global cognition,	High -unclear high -low
	[38] Switzerland	and/or cognitive		AD (4), MCI HE (11), CI	psychomotor, ADL) learning, planning, spatial ) + physical	Center (n.r.), Center (9), home	attention, language, perceptual-	-cognitive functions	or other outcomes, but they learning & memory,	GRADE
	[11]	function and		(3), AD or (2), MCI (4)	(aerobic, interval, stretching, strength	home (n.r.) (6), n.r. (3)	Other: depression, anxiety, motor function	CMDT > physical	can improve DT complex attention,	very low (17)
		transfer to I-ADL		MCI (2)	CG: NI or usual care (6), education resistance, balance ) (12), Tai-chi-	6-52w 4-52w	apathy, agitation, ADL E-ADL,	STT and cognitive	performance. This effect language, and realized seq
		2) provide a rating			(1), placebo (1), cognitive STT (1) Dance (3), EG (2)		QoL Physical : cardiorespiratory	STT improving	only appeared in AD, not in in MCI
		of the "best					fitness, balance, muscle strength,	physical and	MCI. CMDT are more effective
		intervention"			GC : NI (6) and/or activities (12),		flexibility	cognitive functions	on cognitive functions, and
		(physical, cognitive			education (3)				realized sim and seq in HE
		or I-ADL)
		3) evaluate
		modalities (content,
	Untari, 2019 Indonesia [56] Yang, 2019 [61] USA	1) Effects of CMDT on cognitive functions outcomes frequency, duration, intensity, sim/seq) 1) Effects of functional with STT or NI on CMDT compared	SR-MA (11) RCT (11) SR (10) RCT (10)	1145 (n.r.) [65-85] HE (3), MCI (6), AD (1), MCI and AD (1) (4), naMCI (1) 1418 (526 / MCI (6), aMCI [67-87] 892)	Exp: cognitive (computer-based training, memory, VF, visuospatial memory, social interaction, attention, EF) + physical (aerobic, psychomotor, strength, balance, walking, cycling) motor STT (5) psychosocial support (1), placebo (2) CG: NI or usual care (5), cognitive or cognitive or motor STT (2), CG : education (3), usual care (4), Exp: cognitive (i.g., memory skills) + omega 3) cognitive and physical + other (e.g., physical (e.g., aerobic exercise), or	Sim (11) n.r. n.r. Sim (4), seq (6) 8-52w 6-52w Center (10) Grp (10)	activity, mobility, gait, balance, Physical: physical health and Cognitive: global cognition, EF, logical memory, mental abilities, reaction time Cognitive: global cognition, EF, changes in brain cortex atrophy, self-esteem, QoL emotion, motivation, orientation, Other: ADL, E-ADL, cortical working memory, mood,	physical and STT improving STT and cognitive CMDT effective -CMDT effective on CMDT > physical cognitive functions physical and	n.r. n.r.	CCRT n.r. CCRT n.r.
							cardiorespiratory fitness	cognitive functions
	Physical Outcome Booth, 2016 United Kingdom [7]	1) Effects of CMDT on risk of falls	SR-MA (8) RCT (8)	1041 (n.r.) [70-83] Dem (3), AD	Exp: multicomponent cognitive/physical exercise programs (6), Tai-Chi (1), Music (1)	Sim (8) Ind (2), Grp (8) n.r.	Cognitive: global cognition, memory, attention/EF Others: ADL, mood Physical: falls related risk factors (gait, balance, strength, mobility), falls occurrence	CMDT effective CMDT > CG CMDT effective CMDT > physical STT	No difference in cognitive effects according to cognitive status (MCI = n.r. dem)	CCRT (Unclear -JBI-MAStARI Low) (/10) 7,5 [5-10]
				(1), MCI (1),		4-52w
				CI (3)	CG : PA (4), usual care or NI (4)
	Law, 2014	1) Effects of	SR (8)	802 (185 / 617)	Exp: cognitive (memory, processing	Sim (5), seq (3)	Cognitive: global cognition,	CMDT effective	HE: significant benefits on	Personal list
	Australia	CMDT on	RCT (4), NRSI (4)	[62-82]	speed, attention and memory training,	n.r.	memory, subjective measures of	-	general cognitive functions	modified from
	[28] Cognitive and Physical Outcome cognitive functions Lipardo, 2017 1) Effects of China CMDT on falls and functions) cognitive limb strength, gait, (balance, lower [31] fall risk factors	SR (17) RCT (17)	HE (3), Dem (2), MCI (3) 1679 (n.r.) [70 -79] MCI (17)	calculation) + physical (aerobic, balance, flexibility, strength, walking) (8) CG: NI (4), PA (4), CA (4), education (3) Exp: physical STT (6), cognitive computerized STT (4), cognitive traditional intervention (not specified) CG : NI, placebo, education, ST or group-based STT (4), CMDT (3)	Center (4), home (2), unclear (4) 8-52w n.r. n.r. 5-52w n.r.	cognitive impairment, functional status, attention, processing speed, verbal fluency, EF, DT cost Others: ADL Cognitive: global cognitive function, memory, EF limb muscle strength incidence, balance, gait, lower Physical : falls rate and	CMDT effective on physical functions -cognition effects on global and memory, no	compared to active control groups CI: significant benefits on general cognitive functions, lack of comparison Physical STT improved fall-related factors such as outcomes in MCI improve cognitive Cognitive STT did not cognitive function in MCI walking speed and global	Delphi list, JBI-MAStARI PEDro scale (/10) and AHRQ High (1) Medium (7) [7-11] (/13) : 7,8 [7-10]
									CMDT improved balance
									in MCI; inconclusive on
									global cognition and EF

AD: Alzheimer's disease; ADL: activity of daily living; aMCI: amnestic MCI; CA: cognitive activity; CCRT: Cochrane collaboration RoB tool; CI: cognitive impairment; CMDT: cognitive-motor dual-task; Dem: dementia; EF: executive functions; EG: exergame; EPHPP: Effective Public Health Practice Project assessment tool; Grp: group; HE: cognitively healthy elderly; I-ADL: instrumental activities of daily living; Ind: independently; MA : meta-analysis; MCI: mild cognitive impairment; naMCI: non amnestic MCI; NI: no intervention; NRSI: non randomized study of intervention; PA: physical activity; QoL: quality of life; RCT: randomized controlled trial; RoB: risk of bias; Seq: sequential CMDT; Sim: simultaneous CMDT; SR : systematic review; STT: single task training; w: week; "n.r.": not reported.

Table 2 :

 2 methodological quality assessment.

	AMSTAR-2 Criterion

*: AMSTAR 2 critical domains; Y: Yes; P: Partially yes; N: No; n.a.: not applicable; n.r.: not reported.

Acknowledgement and funding

The authors thank the City of Limoges for support. This research received a grant from city of Limoges and the Nouvelle Aquitaine region. The funding source was not involved in the conduct of the research.

Conflict of interest

The authors declare no conflict of interest.

Moderate: more than one non-critical weakness*. The systematic review has more than one weakness but no critical flaws. It may provide an accurate summary of the results of the available studies that were included in the review Low: one critical flaw with or without non-critical weaknesses. The review has a critical flaw and may not provide an accurate and comprehensive summary of the available studies that address the question of interest Critically low: more than one critical flaw with or without non-critical weaknesses. The review has more than one critical flaw and should not be relied on to provide an accurate and comprehensive summary of the available studies