Association between sleep slow-wave activity and in-vivo estimates of myelin in healthy young men.

Sleep has been suggested to contribute to myelinogenesis and associated structural changes in the brain. As a principal hallmark of sleep, slow-wave activity (SWA) is homeostatically regulated but also differs between individuals. Besides its homeostatic function, SWA topography is suggested to reflect processes of brain maturation. Here, we assessed whether interindividual differences in sleep SWA and its homeostatic response to sleep manipulations are associated with in-vivo myelin estimates in a sample of healthy young men. Two hundred twenty-six participants (18-31 y.) underwent an in-lab protocol in which SWA was assessed at baseline (BAS), after sleep deprivation (high homeostatic sleep pressure, HSP) and after sleep saturation (low homeostatic sleep pressure, LSP). Early-night frontal SWA, the frontal-occipital SWA ratio, as well as the overnight exponential SWA decay were computed over sleep conditions. Semi-quantitative magnetization transfer saturation maps (MTsat), providing markers for myelin content, were acquired during a separate laboratory visit. Early-night frontal SWA was negatively associated with regional myelin estimates in the temporal portion of the inferior longitudinal fasciculus. By contrast, neither the responsiveness of SWA to sleep saturation or deprivation, its overnight dynamics, nor the frontal/occipital SWA ratio were associated with brain structural indices. Our results indicate that frontal SWA generation tracks inter-individual differences in continued structural brain re-organization during early adulthood. This stage of life is not only characterized by ongoing region-specific changes in myelin content, but also by a sharp decrease and a shift towards frontal predominance in SWA generation.

Hippocampal metabolic subregions and networks: Behavioral, molecular, and pathological aging profiles.

INTRODUCTION: Hippocampal local and network dysfunction is the hallmark of Alzheimer's disease (AD). METHODS: We characterized the spatial patterns of hippocampus differentiation based on brain co-metabolism in healthy elderly participants and demonstrated their relevance to study local metabolic changes and associated dysfunction in pathological aging. RESULTS: The hippocampus can be differentiated into anterior/posterior and dorsal cornu ammonis (CA)/ventral (subiculum) subregions. While anterior/posterior CA show co-metabolism with different regions of the subcortical limbic networks, the anterior/posterior subiculum are parts of cortical networks supporting object-centered memory and higher cognitive demands, respectively. Both networks show relationships with the spatial patterns of gene expression pertaining to cell energy metabolism and AD's process. Finally, while local metabolism is generally lower in posterior regions, the anterior-posterior imbalance is maximal in late mild cognitive impairment with the anterior subiculum being relatively preserved. DISCUSSION: Future studies should consider bidimensional hippocampal differentiation and in particular the posterior subicular region to better understand pathological aging.

Genetic risk for insomnia is associated with objective sleep measures in young and healthy good sleepers.

Insomnia disorder (ID) is the second most common neuropsychiatric disorder. Its socioeconomic burden is enormous while diagnosis and treatment are difficult. A novel approach that reveals associations between insomnia genetic propensity and sleep phenotypes in youth may help understand the core of the disease isolated from comorbidities and pave the way for new treatments. We obtained quantitative nocturnal sleep electroencephalogram (EEG) features in 456 participants (18-31y, 49 women). Sleep EEG was recorded during a baseline night following at least 7 days of regular sleep times. We then assessed daytime sleep onset latency in a subsample of N = 359 men exposed to manipulations affecting sleep pressure. We sampled saliva or blood for polygenic risk score (PRS) determination. The PRS for ID was computed based on genome-wide common single nucleotide polymorphism assessments. Participants also completed a battery of behavioral and cognitive tests. The analyses revealed that the PRS for ID was negatively associated with cumulated EEG power in the delta (0.5-4 Hz) and theta (4-8 Hz) bands across rapid eye movement (REM) and non-REM sleep (p ≤ .0026; ß ≥ -0.13) controlling for age, sex and BMI. The PRS for ID was also negatively associated with daytime likelihood of falling asleep (ß = -0.19, p = .0009). Other explorations for associations with non-baseline-nights, cognitive measures, and mood did not yield significant results. These results propose that the need or the ability to fall asleep and to generate slow brain activity during sleep may constitute the core sleep-related risk factors for developing ID.

Evolution of anosognosia in alzheimer's disease and its relationship to amyloid.

OBJECTIVE: Unawareness, or anosognosia, of memory deficits is a challenging manifestation of Alzheimer's disease (AD) that adversely affects a patient's safety and decision-making. However, there is a lack of consensus regarding the presence, as well as the evolution, of altered awareness of memory function across the preclinical and prodromal stages of AD. Here, we aimed to characterize change in awareness of memory abilities and its relationship to beta-amyloid (Aß) burden in a large cohort (N = 1,070) of individuals across the disease spectrum. METHODS: Memory awareness was longitudinally assessed (average number of visits = 4.3) and operationalized using the discrepancy between mean participant and partner report on the Everyday Cognition scale (memory domain). Aß deposition was measured at baseline using [18F]florbetapir positron emission tomographic imaging. RESULTS: Aß predicted longitudinal changes in memory awareness, such that awareness decreased faster in participants with increased Aß burden. Aß and clinical group interacted to predict change in memory awareness, demonstrating the strongest effect in dementia participants, but could also be found in the cognitively normal (CN) participants. In a subset of CN participants who progressed to mild cognitive impairment (MCI), heightened memory awareness was observed up to 1.6 years before MCI diagnosis, with memory awareness declining until the time of progression to MCI (-0.08 discrepant-points/yr). In a subset of MCI participants who progressed to dementia, awareness was low initially and continued to decline (-0.23 discrepant-points/yr), reaching anosognosia 3.2 years before dementia onset. INTERPRETATION: Aß burden is associated with a progressive decrease in self-awareness of memory deficits, reaching anosognosia approximately 3 years before dementia diagnosis. ANN NEUROL 2020;87:267-280.

Boosting Familiarity-Based Memory Decisions in Alzheimer's Disease: The Importance of Metacognition.

OBJECTIVE: Recent studies in Alzheimer's disease (AD) have suggested that AD patients are not always able to rely on their feeling of familiarity to improve their memory decisions to the same extent as healthy participants. This underuse of familiarity in AD could result from a learned reinterpretation of fluency as a poor cue for memory that would prevent them to attribute a feeling of fluency to a previous encounter. The primary goal of this study was to determine whether AD patients could relearn the association between processing fluency and past exposure after being repeatedly exposed to situations where using this association improves the accuracy of their memory decisions. METHOD: Thirty-nine patients with probable AD were recruited and asked to complete several recognition tests. During these tests, participants were put either in a condition where the positive contingency between fluent processing and previous encounters with an item was systematically confirmed (intervention condition) or in a condition where there was no correlation between fluency and prior exposure (control condition). The efficacy of the intervention was evaluated at three time points (baseline, posttest, and 3-month follow-up). RESULTS: Our results indicated that all AD patients do not benefit to the same extent from the training. Two variables appeared to influence the likelihood that participants increase and maintain their reliance on the fluency cues after the intervention: the ability to detect the fluency manipulation and the preservation of implicit metacognitive skills. CONCLUSION: These findings indicate the importance of metacognition for inferential attribution processes in memory.

Familiarity in Mild Cognitive Impairment as a Function of Patients' Clinical Outcome 4 Years Later.

OBJECTIVES: The current study addresses the nature of memory difficulties in amnestic mild cognitive impairment (aMCI). Whereas recollection is consistently found to be impaired in aMCI, the results on familiarity are divergent. One potential factor that could explain this divergence in findings relates to the heterogeneity of aMCI patients, so that only those aMCI patients who develop Alzheimer disease (AD) may present with impaired familiarity. The present study aimed at testing this hypothesis. METHODS: A group of 45 aMCI patients and a group of 26 healthy older adults performed a verbal recognition memory test with the Remember/Know paradigm to assess recollection and familiarity processes. All participants were followed for 4 years with clinical and neuropsychological testing. At the end of follow-up, 22 aMCI patients progressed to AD and 23 aMCI patients remained stable. Initial memory performance was compared between the 3 groups. RESULTS: Whereas recollection was severely diminished in all aMCI patients, familiarity accuracy (and consequently global recognition accuracy) was found to be impaired only in aMCI patients who subsequently developed AD. CONCLUSION: These findings suggest that the enrichment of the aMCI population with predementia stage patients may modulate the likelihood to observe familiarity deficits, and impaired global recognition accuracy may accompany incipient AD.

Efficacy of Cognitive Rehabilitation Versus Usual Treatment at Home in Patients With Early Stages of Alzheimer Disease.

INTRODUCTION: Assessing the benefit of cognitive rehabilitation (CR) remains difficult. METHOD: An observational study was conducted in 33 patients with early-stage Alzheimer disease and their caregiver included in a clinical CR program at home, compared to 17 patients who received usual treatment. Evaluation of patient's dependence and objective and subjective caregiver's burden was performed by the caregiver with a research tool focusing on impairment in daily activities related to cognitive deficits. RESULTS: Repeated measures analysis of variance showed a time by group interaction (P < .05), with decreased patient's dependence for adapted activities at 1 year in the CR group. Lawton scale for daily activities showed also a time by group interaction (P < .05), with increased dependence at 1 year in the control group. There was a significant decrease in Mini-Mental State Examination scores in both groups at 1-year follow-up (P < .05). Concerning caregiver's subjective burden, there was a trend for the time by group interaction (P = .07), and post hoc Tukey test showed that subjective burden was decreased in the CR group (P < .05). This was confirmed by nonparametric Mann-Whitney analysis on differences between follow-up and baseline evaluation (P < .05). CONCLUSION: This observational study in a clinical setting is in line with the benefit of CR reported in recent randomized controlled trials. The benefit obtained for adapted daily activities remained after 1 year, even if global cognition declined. Moreover, caregiver's subjective burden related to all relevant daily activities evaluated within the CR program was decreased after 1 year in our clinical setting.

Relationship between brain AD biomarkers and episodic memory performance in healthy aging.

The presence of brain biomarkers can be observed decades before the first clinical symptoms of Alzheimer's disease (AD). We aimed to determine whether associations between biomarkers and episodic memory performance already exist in a healthy late middle-aged population or only in participants over 60 years old. Performance at the Free and Cued Selective Reminding Test [FCSRT], the Logical Memory test and the Mnemonic Similarity Task [MST] was determined in sixty healthy participants (50-70 y.) with a negative status for amyloid-beta (Aß) biomarker. We assessed Aß cortical level and tau/neuroinflammation burden using PET scanner, and hippocampal atrophy with MRI scanner. Generalized linear mixed models showed that MST scores (recognition and pattern separation) were positively associated with hippocampal volume in participants over 60 years. No association between memory performance and Aß and tau/neuroinflammation burden was found in the older or in the younger age group. This suggests that visual recognition memory and discrimination of lures may constitute early cognitive markers of memory decline in an older population.

Impaired explicit self-awareness but preserved behavioral regulation in patients with Alzheimer disease.

OBJECTIVES: Impairments of metacognitive skills represent a critical symptom in Alzheimer Disease (AD) because it frequently results in a lack of self-awareness. However, recent findings suggest that, despite an inability to explicitly estimate their own cognitive functioning, patients might demonstrate some implicit recognition of difficulties. In this study, we tested whether a behavioral dissociation between explicit and implicit measures of metacognition can be found in both healthy older controls (n = 20) and AD patients (n = 20). METHODS: Our two groups of participants (AD vs. Controls) were asked to complete a forced-choice perceptual identification test and to explicitly rate their confidence in each decision (i.e. explicit measure of metacognition). Moreover, they also had the opportunity to ask for a cue to help them decide if their response was correct (i.e. implicit measure of metacognition). RESULTS: Data revealed that all participants asked for a cue more often after an incorrect response than after a correct response in the forced-choice identification test, indicating a good ability to implicitly introspect on the results of their cognitive operations. On the contrary, only healthy participants displayed metacognitive sensitivity when making explicit confidence judgments. CONCLUSION: Our findings suggest that implicit metacognition may be less affected than explicit metacognition in Alzheimer's disease.

Age-related differences in the neural correlates of vivid remembering.

When recollecting events, older adults typically report similar memory vividness levels as young adults, while they actually retrieve fewer episodic details. This suggests that young and older adults use episodic details differently to calibrate their vividness judgements. Capitalizing on the idea that remembering reactivates brain regions that initially processed details at encoding, the current fMRI study sought to examine these age-related changes in the basis of vivid recollection. At encoding, young and older adults saw pictures associated with labels and these labels were then used as retrieval cues for recalling the associated pictures and making memory vividness judgments. Results showed that highly vivid memories were associated with greater activity in the precuneus in young than older adults. Furthermore, the direct comparison between encoding and retrieval patterns of activity using Representational Similarity Analyses revealed stronger item-specific reactivation in the posterior cingulate/retrosplenial cortex in young than older adults. Taken together, these results provide new evidence that aging is associated with reduced reinstatement of activity in brain regions that processed the encoding of complex stimuli, but older individuals judge these impoverished memory representations as subjectively vivid.

In vivo imaging of synaptic loss in Alzheimer's disease with [18F]UCB-H positron emission tomography.

PURPOSE: Loss of brain synapses is an early pathological feature of Alzheimer's disease. The current study assessed synaptic loss in vivo with positron emission tomography and an 18F-labelled radiotracer of the synaptic vesicle protein 2A, [18F]UCB-H. METHODS: Twenty-four patients with mild cognitive impairment or Alzheimer's disease and positive [18F]Flutemetamol amyloid-PET were compared to 19 healthy controls. [18F]UCB-H brain uptake was quantified with Logan graphical analysis using an image-derived blood input function. SPM12 and regions-of-interest (ROI) analyses were used for group comparisons of regional brain distribution volumes and for correlation with cognitive measures. RESULTS: A significant decrease of [18F]UCB-H uptake was observed in several cortical areas (11 to 18% difference) and in the thalamus (16% difference), with the largest effect size in the hippocampus (31% difference). Reduced hippocampal uptake was related to patients' cognitive decline (ROI analysis) and unawareness of memory problems (SPM and ROI analyses). CONCLUSIONS: The findings thus highlight predominant synaptic loss in the hippocampus, confirming previous autopsy-based studies and a recent PET study with an 11C-labelled SV2A radiotracer. [18F]UCB-H PET allows to image in vivo synaptic changes in Alzheimer's disease and to relate them to patients' cognitive impairment.

Exploring scoring methods for research studies: Accuracy and variability of visual and automated sleep scoring.

Sleep studies face new challenges in terms of data, objectives and metrics. This requires reappraising the adequacy of existing analysis methods, including scoring methods. Visual and automatic sleep scoring of healthy individuals were compared in terms of reliability (i.e., accuracy and stability) to find a scoring method capable of giving access to the actual data variability without adding exogenous variability. A first dataset (DS1, four recordings) scored by six experts plus an autoscoring algorithm was used to characterize inter-scoring variability. A second dataset (DS2, 88 recordings) scored a few weeks later was used to explore intra-expert variability. Percentage agreements and Conger's kappa were derived from epoch-by-epoch comparisons on pairwise and consensus scorings. On DS1 the number of epochs of agreement decreased when the number of experts increased, ranging from 86% (pairwise) to 69% (all experts). Adding autoscoring to visual scorings changed the kappa value from 0.81 to 0.79. Agreement between expert consensus and autoscoring was 93%. On DS2 the hypothesis of intra-expert variability was supported by a systematic decrease in kappa scores between autoscoring used as reference and each single expert between datasets (.75-.70). Although visual scoring induces inter- and intra-expert variability, autoscoring methods can cope with intra-scorer variability, making them a sensible option to reduce exogenous variability and give access to the endogenous variability in the data.

The Rise of Synaptic Density PET Imaging.

Many neurological disorders are related to synaptic loss or pathologies. Before the boom of positrons emission tomography (PET) imaging of synapses, synaptic quantification could only be achieved in vitro on brain samples after autopsy or surgical resections. Until the mid-2010s, electron microscopy and immunohistochemical labelling of synaptic proteins were the gold-standard methods for such analyses. Over the last decade, several PET radiotracers for the synaptic vesicle 2A protein have been developed to achieve in vivo synapses visualization and quantification. Different strategies were used, namely radiolabelling with either 11C or 18F, preclinical development in rodent and non-human primates, and binding quantification with different kinetic modelling methods. This review provides an overview of these PET tracers and underlines their perspectives and limitations by focusing on radiochemical aspects, as well as preclinical proof-of-concept and the main clinical outcomes described so far.

Interactions with the integrative memory model.

The integrative memory model formalizes a new conceptualization of memory in which interactions between representations and cognitive operations within large-scale cerebral networks generate subjective memory feelings. Such interactions allow to explain the complexity of memory expressions, such as the existence of multiples sources for familiarity and recollection feelings and the fact that expectations determine how one recognizes previously encountered information.

Anosognosia and default mode subnetwork dysfunction in Alzheimer's disease.

Research on the neural correlates of anosognosia in Alzheimer's disease varied according to methods and objectives: they compared different measures, used diverse neuroimaging modalities, explored connectivity between brain networks, addressed the role of specific brain regions or tried to give support to theoretical models of unawareness. We used resting-state fMRI connectivity with two different seed regions and two measures of anosognosia in different patient samples to investigate consistent modifications of default mode subnetworks and we aligned the results with the Cognitive Awareness Model. In a first study, patients and their relatives were presented with the Memory Awareness Rating Scale. Anosognosia was measured as a patient-relative discrepancy score and connectivity was investigated with a parahippocampal seed. In a second study, anosognosia was measured in patients with brain amyloid (taken as a disease biomarker) by comparing self-reported rating with memory performance, and connectivity was examined with a hippocampal seed. In both studies, anosognosia was consistently related to disconnection within the medial temporal subsystem of the default mode network, subserving episodic memory processes. Importantly, scores were also related to disconnection between the medial temporal and both the core subsystem (participating to self-reflection) and the dorsomedial subsystem of the default mode network (the middle temporal gyrus that might subserve a personal database in the second study). We suggest that disparity in connectivity within and between subsystems of the default mode network may reflect impaired functioning of pathways in cognitive models of awareness.

Characterization of a temporoparietal junction subtype of Alzheimer's disease.

Alzheimer's disease (AD) subtypes have been described according to genetics, neuropsychology, neuropathology, and neuroimaging. Thirty-one patients with clinically probable AD were selected based on perisylvian metabolic decrease on FDG-PET. They were compared to 25 patients with a typical pattern of decreased posterior metabolism. Tree-based machine learning was used on those 56 images to create a classifier that was subsequently applied to 207 Alzheimer's Disease Neuroimaging Initiative (ADNI) patients with AD. Machine learning was also used to discriminate between the two ADNI groups based on neuropsychological scores. Compared to AD patients with a typical precuneus metabolic decrease, the new subtype showed stronger hypometabolism in the temporoparietal junction. The classifier was able to distinguish the two groups in the ADNI population. Both groups could only be distinguished cognitively by Trail Making Test-A scores. This study further confirms that there is more than a typical metabolic pattern in probable AD with amnestic presentation.

Loss of DPP6 in neurodegenerative dementia: a genetic player in the dysfunction of neuronal excitability.

Emerging evidence suggested a converging mechanism in neurodegenerative brain diseases (NBD) involving early neuronal network dysfunctions and alterations in the homeostasis of neuronal firing as culprits of neurodegeneration. In this study, we used paired-end short-read and direct long-read whole genome sequencing to investigate an unresolved autosomal dominant dementia family significantly linked to 7q36. We identified and validated a chromosomal inversion of ca. 4 Mb, segregating on the disease haplotype and disrupting the coding sequence of dipeptidyl-peptidase 6 gene (DPP6). DPP6 resequencing identified significantly more rare variants-nonsense, frameshift, and missense-in early-onset Alzheimer's disease (EOAD, p value = 0.03, OR = 2.21 95% CI 1.05-4.82) and frontotemporal dementia (FTD, p = 0.006, OR = 2.59, 95% CI 1.28-5.49) patient cohorts. DPP6 is a type II transmembrane protein with a highly structured extracellular domain and is mainly expressed in brain, where it binds to the potassium channel Kv4.2 enhancing its expression, regulating its gating properties and controlling the dendritic excitability of hippocampal neurons. Using in vitro modeling, we showed that the missense variants found in patients destabilize DPP6 and reduce its membrane expression (p < 0.001 and p < 0.0001) leading to a loss of protein. Reduced DPP6 and/or Kv4.2 expression was also detected in brain tissue of missense variant carriers. Loss of DPP6 is known to cause neuronal hyperexcitability and behavioral alterations in Dpp6-KO mice. Taken together, the results of our genomic, genetic, expression and modeling analyses, provided direct evidence supporting the involvement of DPP6 loss in dementia. We propose that loss of function variants have a higher penetrance and disease impact, whereas the missense variants have a variable risk contribution to disease that can vary from high to low penetrance. Our findings of DPP6, as novel gene in dementia, strengthen the involvement of neuronal hyperexcitability and alteration in the homeostasis of neuronal firing as a disease mechanism to further investigate.

Do Alzheimer's Disease Patients Benefit From Prior-Knowledge in Associative Recognition Memory?

OBJECTIVES: Although the influence of prior knowledge on associative memory in healthy aging has received great attention, it has never been studied in Alzheimer's disease (AD). This study aimed at assessing whether AD patients could benefit from prior knowledge in associative memory and whether such benefit would be related to the integrity of their semantic memory. METHODS: Twenty-one AD patients and 21 healthy older adults took part in an associative memory task using semantically related and unrelated word pairs and were also submitted to an evaluation of their semantic memory. RESULTS: While participants of both groups benefited from semantic relatedness in associative discrimination, related pairs recognition was significantly predicted by semantic memory integrity in healthy older adults only. CONCLUSIONS: We suggest that patients benefitted from semantic knowledge to improve their performance in the associative memory task, but that such performance is not related to semantic knowledge integrity evaluation measures because the two tasks differ in the way semantic information is accessed: in an automatic manner for the associative memory task, with automatic processes thought to be relatively preserved in AD, and in a controlled manner for the semantic knowledge evaluation, with controlled processes thought to be impaired in AD. (JINS, 2019, 25, 443-452).

Efficacy of Cognitive Rehabilitation in Alzheimer Disease: A 1-Year Follow-Up Study.

INTRODUCTION: The benefit of cognitive rehabilitation (CR) for patients with early-stage Alzheimer disease (AD) remains difficult to assess. METHOD: An observational, prospective study was conducted in a sample of 52 patients with AD included in a clinical, individualized CR program. Cognitive rehabilitation consisted of 1 weekly session during 3 months at home, followed by 1 monthly contact for 9 months. Rehabilitation techniques were used by experienced therapists to adapt activities important for the patient. Evaluation of patient's dependence in activities and objective and subjective caregiver's burden was performed with a research quantitative scale immediately after the intervention and at 6-month and 1-year follow-up. RESULTS: Analyses with repeated measure analysis of variance showed decreased patient's dependence for adapted activities at 3 months, 6 months, and 1 year. Objective and subjective percentage of caregiver's burden was also decreased at all evaluations with our research functional scale, while there was no change on Zarit's burden scale. Global cognition slightly decreased over 1 year. CONCLUSIONS: This observational study in a clinical setting is in line with the benefit of CR for patients with mild AD reported in recent randomized controlled trials. The benefit obtained for adapted activities remained after 1 year, even if global cognition declined. Moreover caregiver's burden related to all individually relevant daily activities (from a list of 98) evaluated within the CR program was decreased after 1 year. Those preliminary results emphasize the importance of choice for the measurement instrument to report CR efficacy and claim for further validation of such tools.

Gait symmetry in the dual task condition as a predictor of future falls among independent older adults: a 2-year longitudinal study.

BACKGROUND: Given the potential consequences of falls among older adults, a major challenge is to identify people at risk before the first event. In this context, gait parameters have been suggested as markers of fall risk. AIM: To examine, among older people, the prospective relationship between gait patterns assessed in comfortable and challenging walking conditions, and future fall(s). METHOD: A total of 105 adults older than 65 years, living independently at home and without a recent fall history were included in a 2-year, longitudinal, observational study. All underwent physical and functional assessment. Gait speed, stride length, frequency, symmetry and regularity and Minimum Toe Clearance (MTC) were recorded in comfortable (CW), fast (FW) and dual task walking (DTW) conditions. Gait parameter changes occurring between CW and FW and between CW and DTW were calculated and expressed in percent. DTW cost was calculated as the change of DTW relative to CW. Fall events were recorded using fall diaries. Comparisons according to fall occurrence were performed by means of univariate analysis and multivariate binary logistic regression analysis. RESULTS: Two-year follow-up was available for 96 participants, of whom 35 (36.5%) fell at least once. Comparative analysis showed that future fallers had shorter FW stride length and higher symmetry DTW cost than non-fallers (p < 0.05). Binary logistic regression analysis showed that each additional percent of stride symmetry cost was associated with an increase in future fall risk (odds ratio 1.018, 95% Confidence Interval (CI) 1.002-1.033; p = 0.027). DISCUSSION: Our results confirm the association between a symmetry decrease in DTW and future fall(s). Indeed in this study, the mean symmetry DTW cost in fallers is almost 20% higher than in non-fallers, meaning a fall risk that is around 36% higher than among non-fallers. CONCLUSION: This exploratory study shows the usefulness of considering gait parameters, particularly symmetry in challenging walking conditions, for early identification of future fallers.