Abstract
INTRODUCTION
Early detection of Alzheimer’s disease (AD) is a key component of efficient prevention [1]. Recently, subjective cognitive impairment (SCI), where patients do not have objective findings of cognitive impairment, has been defined as a prodromal state of mild cognitive impairment (MCI) [2]. Individuals with SCI are a heterogeneous group of patients who have a higher risk of developing dementia compared to individuals who have no cognitive complaint [2]. SCI is considered the earliest clinical stage of AD because AD is the most common cause of dementia in individuals over age 65 [1–4] and it has been associated with AD biomarkers [3–8].
In addition to cognitive impairment, gait disturbances are also associated with the occurrence of AD [9]. Gait parameters, such as stride time variability, have been used as biomarkers of early stages of AD. An increased variability of stride time (i.e., gait cycle duration) is a disturbance, which is a feature of gait of MCI individuals [10, 11]. Stride time variability is a sensitive and specific marker of cortical gait control [12]. Changes in variability of stride time have been associated with hippocampal volume in cognitively healthy individuals and in individuals with MCI [13–16], underscoring that the hippocampus is not only involved in memory processes but also in gait control.
Dual task conditions have been applied to demonstrate the involvement of cognition in gait control [17, 18]. The principle of a dual task gait paradigm is to compare the task performance while walking and simultaneously executing an attention-demanding task, like a cognitive task, to the performance of walking while under routine conditions [17]. Changes in gait performance under dual tasking conditions are usually interpreted as interference related to competing demands for cognitive resources that are otherwise needed for both tasks [17, 18]. Individuals with MCI, specifically those with the amnestic form, have demonstrated high stride time variability, particularly under dual task conditions [19].
Subjective memory impairment (SMI), which is a subdomain of SCI, is the most prevalent complaint of AD individuals [1–4]. SMI may be expressed by individuals themselves and/or by their relatives with the latter complaint reflecting a more objective change in memory [20, 21]. SCI and increased stride time variability are both markers of the onset of AD. Furthermore, stride time variability is associated with memory performance and hippocampal volume. The purpose of this study is to examine the association of stride time variability under single and dual task conditions between individuals with and without SMI. We hypothesized that individuals with SMI would have a greater stride time variability compared to individuals who were cognitively healthy, especially under dual task condition and when memory impairments are reported by the relatives ofindividuals.
METHODS
Participants
Between November 2009 and November 2015, 875 individuals were recruited in the GAIT study. The study procedure has been previously described in detail [22]. Participants were referred from the memory clinic of Angers University Hospital, France. The eligibility criteria were: age 65 years and over, ambulatory, adequate understanding of French, and no acute medical illness in the past month. For the present analysis, exclusion criteria were: uncompleted memory complaint questionnaire, MCI, dementia, extrapyramidal rigidity of the upper limbs, neurological and psychiatric diseases other than cognitive impairment, severe medical conditions affecting walking, inability to walk 15 minutes unassisted, or the presence of depressive symptoms defined by a 4-item Geriatric Depression Scale score above 1 [23]. The diagnosis of dementia and MCI were made during multidisciplinary meetings involving geriatricians, neurologists, and neuropsychologists of Angers University Memory Clinic, and was based on the aforementioned neuropsychological tests, physical examination findings, blood tests, and MRI of the brain. MCI was diagnosed according to the criteria detailed by Dubois et al. [24] and dementia was diagnosed using the NINCDS/ADRDA criteria [25]. After applying exclusion criteria, a total of 126 (14.4%) participants were selected.
Clinical assessment
All selected participants received a full-standardized medical examination, a neuropsychological and gait assessment, and MRI of the brain. Age, sex, height in meters, weight in kilograms, the number of medications taken daily (which is an objectively accessible and inexpensive strategy to assess the morbidity burden among older adults) [26], use of psychoactive drugs (i.e., benzodiazepines, antidepressants, or neuroleptics), fear of falling using the single question: “Are you afraid of falling?” with a binary answer (i.e., yes versus no) [27], history of falls— defined as unintentionally coming to rest on the ground, floor, or other lower level— over the past year were recorded [28]. All these clinical characteristics are considered as potential confounders for gait variability [11, 26–28]. SMI was recorded using a standardized self-administered questionnaire composed of 6 items and exploring memory complaints expressed by the participants and/or by their relatives who accompanied them to the memory clinic. The questionnaire in format paper was given to each GAIT participant at his or her arrival in the memory clinic. All items corresponded to a question with a forced choice in closed-ended format (i.e., yes or no). The English version of the questionnaire is presented in the Supplementary Material. Three questions specifically explored subjective memory complaint and were used to assess memory complaints in three groups: participants (individuals who answered yes to the following question: do you have persistent memory issues in your daily living activities? Do you have issues learning new information?), participant’s relative (individuals who answered yes to the question: has your family noted that your relative has persistent memory issue?), and participant plus participant’s relative complaint (answer yes to the question: has your family noted that you have persistent memory issue? And at least one answer yes to the following question: do you have persistent memory issues in your daily living activities? Do you have issues learning newinformation?).
Neuropsychological assessment
A neuropsychological assessment was performed on each participant during a face-to-face interview by a neuropsychologist. The following standardized tests were used to probe several aspects of cognitive function: Mini-Mental State Examination (MMSE) [29], Frontal Assessment Battery (FAB) [30], Alzheimer’s Disease Assessment Scale–Cognitive subscale (ADAS-cog) [31], Trail Making Test (TMT) parts A and B [32], French version of the Free and Cued Selective Reminding Test [33, 34], and Instrumental Activities of Daily Living scale (IADL) [35]. Participants who had normal neuropsychological and functional performances were considered as cognitively healthy.
Gait assessment
Coefficient of variation (CoV = (standard deviation / mean)×100) of stride time and mean value of walking speed were recorded at self-selected usual pace and while dual tasking using a computerized walkway with embedded pressure sensors (GAITRite® Gold walkway, 972 cm long, active electronic surface area 792×610 cm, total 29,952 pressure sensors, scanning frequency 60 Hz, CIR System, Havertown, PA) according to the European guidelines for spatio-temporal gait analysis in older adults [36]. Briefly, the participants were asked to walk at in a quiet, well-lit corridor wearing their own footwear. The participants completed one trial for each walking condition. The number of consecutive gait cycles for both the left and right side recorded was ranged from 6 to 10. To avoid acceleration and deceleration effects, participants started walking one meter before reaching the electronic walkway and completed their walk one meter beyond it. The cognitive task used while walking was a simple arithmetic task, which was backward counting aloud starting from 50.
Ethics
Participants in the study were included after having given their written informed consent for research. The study was conducted in accordance with the ethical standards set forth in the Helsinki Declaration (1983). Angers local Ethical Committee, France, approved the study protocol.
Statistics
The participants’ characteristics were summarized using means and standard deviations or frequencies and percentages, as appropriate. For the current analysis, participants were classified into 4 groups based on SMI, as follows: No SMI, SMI expressed by participants, SMI expressed by participant’s relative, and SMI expressed by participants and participant’s relative. First, between-group comparisons were performed using Kruskal-Wallis, unpaired t-test, Mann-Whitney or Chi-square test, as appropriate. p-values less than 0.0029 were considered as statistically significant after adjustments for multiple comparisons (n = 17). Second, multiple linear regression analyses were performed to examine the association between CoV of stride time (dependent variable) and SMI (independent variable) adjusted on the participants’ characteristics (i.e., age, sex, BMI, number of medications taken daily, use of psychoactive drugs, fear of falling and history of falls) and walking speed. p-values less than 0.05 were considered as statistically significant for linear regressions. All statistics were performed using SPSS (version 23.0; SPSS, Inc., Chicago, IL).
RESULTS
Table 1 shows the participants characteristics according to the classification of SMI (i.e., No SMI, SMI expressed by participants, SMI expressed by participant’s relative, and SMI expressed by participants and participant’s relative). There was no significant difference between groups. Only a trend was found for the number of drugs taken daily. The number of medications taken daily was greater in the group with SMI (p = 0.005) as compared to participants without SMI. Results of multiple linear regressions showing the association between CoV of stride time and types of SMI adjusted on participants’ characteristics were reported in Table 2. Only participants with relatives who reported SMI was significantly associated with greater CoV of stride time while backward counting (p = 0.038). When all participants with SMI were polled together in the multiple linear regression, no significant association was reported (Coefficient of regression beta = 0.48 with 95% confidence interval [–1.38;2.34] and p = 0.607).
DISCUSSION
The findings show that SMI was significantly associated with increased gait variability only when SMI was expressed by participant’s relative and under dual-task condition. No other significant association was found. This finding is partially consistent with our a priori hypothesis and the literature.
Dual tasking is used to measure the involvement of cognitive function in gait control [17, 18]. It represents a more sensitive walking condition compared to usual walking, as this condition is associated with the very early onset of an abnormal involvement of cognitive function in gait control. Thus, our results confirm the assumption that there is an association between dual task walking conditions and SMI, suggesting that the very early stage of cognitive decline like SMI is related to increased gait variability. However, this association must be considered carefully. Indeed, only SMI expressed by participant’s relative was associated with a greater stride time variability. It is possible that this method of reporting memory impairment is less subjective when compared to a situation where an individual with concerns about memory impairment reports SMI. Thus, it could be suggested that an individual’s subjective memory concern reflects a more accurate description of his/her cognitive impairment as compared to an individual with memory problems whose relative has concerns about their memory because the latter situation is associated with day-to-day situations. In addition, it is possible that anosognosia could be present in the earlier stage of cognitive dysfunction, and thus, individuals with memory impairments may minimize their cognitive deficits [37, 38]. However, we did not find a significant association between memory impairments expressed both by participants and their relatives and greater (i.e., worse performance) stride time variability. The main explanation for the absence of this association could reflect the fact that a participant’s complaint may precipitate a complaint by his/her relative, and thus is not truly based on a memory deficit. The association between SMI expressed by participant’s relative and greater gait variability under dual-task condition confirms the previous relationship reported between memory and gait control [13–16, 19]. Lower stride time variability reflects automatic walking process requiring low cognitive demands, whereas high stride time variability is related to highly demanding walking tasks such as walking while counting backwards [12]. Our results are in line with the model that suggests that precise gait control requires memory integrity. SCI is considered to be a prodromal stage of MCI and thus reflects the earliest symptom of cognitive impairment. SMI is a subdomain of SCI and is therefore the primary symptom of memory impairment. We suggest that this first symptom of memory dysfunction may cause gait control impairment only under dual task conditions. The hippocampus is a key human brain region involved in memory and locomotion [39–41]. Recently, hippocampal volume has been associated with stride time variability among cognitively healthy individuals [16]. Similarly, in AD, the hippocampus constitutes one of the first brain areas affected by neurodegenerative lesions, causing its atrophy, which explains why hippocampal abnormality is considered as a biomarker of AD [42]. Interestingly, older adults whose relatives report memory complaints also have reduced hippocampalvolume [43].
Our study has some limitations. First, there are small groups of individuals without SMI and with participant’s relative SMI. Second, while this study is the first to demonstrate an association between SMI and stride time variability, the cross-sectional design does not provide information about causal relationship between memory complaints and increased stride time variability under dual tasking conditions. Third, the participants included in the GAIT study were referred to the recruitment center for the evaluation of their cognition. Thus, participants who were defined as having no memory impairment may still have an undiagnosed cognitive complaint. Finally, the presence of the complaints made by a patient’s relatives may be biased by lack of perception and/or anosognosia of the participants because the group of individuals who were classified on the basis of a relative’s complaint group was determined by a positive answer inferred from the self-administered questionnaire by the participant and not the by participant’s relative.
CONCLUSION
This study found a specific association between SMI expressed by participant’s relative and a greater stride time variability while dual tasking, confirming that gait performance is associated with memory performance, which is simultaneously impaired. However, this association must be considered carefully because no other significant association was found and it is the first time that this association is reported. The results of this study suggest that change in gait performance while dual tasking may be used as a biomarker of earliest stage of AD.
Footnotes
ACKNOWLEDGMENTS
The study was financially supported by the French Ministry of Health (Projet Hospitalier de Recherche Clinique national n°2009-A00533-54). Gilles Allali is funded by a grant from the Baasch-Medicus Foundation. The sponsors had no role in the design and conduct of the study, in the collection, management, analysis, and interpretation of the data, or in the preparation, review, or approval of the manuscript.
