Our results show a difference in rates of change in gait and tapping speed with aging between MCI converters and non-converters. Further, a change point was identified where acceleration in the decline of gait speed occurs approximately 12 years prior to MCI onset in a combined analysis for men and women. Change points occurred approximately 14 years prior to MCI onset in men and approximately 6 years for women. Although change points were found with tapping, this occurred after the onset of cognitive impairment in most analyses (the association of this change with the onset of later dementia was not assessed in our current analysis). This suggests that change in the rate of decline in gait speed may be a sensitive marker of cognitive changes distinct from the general motor slowing demonstrated with tapping speed.
Men and women were found to have different change points. There was no significant difference in follow-up time or time to MCI conversion to account for these differences. One possible explanation is that there is a difference in baseline gait speed in women between converters and non-converters, suggesting that the change point may have occurred in women prior to the start of this study. It is possible we may have found an earlier change point for women if we had a larger sample with longer duration of follow-up. Another possibility is that the different change points may be attributed to underlying gender-specific physiological differences.
Several studies have examined the prediction of baseline gait speed and other motor signs to the future development of cognitive impairment6, 7, 28
or dementia8, 29
using survival analysis or linear regression analysis. We are not aware of other studies that have prospectively examined the rates of change
in gait speed or other motor signs and their relationship to incident MCI. We used up to 20 years of data to determine rates of motor changes and to identify the earliest time at which these changes occur in relation to clinical findings of cognitive impairment.
The sensitivity of gait changes to early cognitive changes may be best understood if gait is viewed as a complex cognitive task.30–32
Gait requires an interplay of attention, executive function and visuospatial function, as well as the motor processing functions of the motor cortex, basal ganglia and cerebellum. Therefore, the same mechanisms that underlie decline in cognitive functioning may be associated with decline in gait. Gait speed change may thus be a bellwether of the efficiency of the central integration of multiple cognitive domains needed for this complex task. Decline in gait speed may also be viewed as part of a larger construct of physical frailty in the elderly. Physical frailty is common in the elderly and includes measures of gait speed, strength, body composition and fatigue and is associated with incident dementia and AD pathology.33
The underlying pathophysiology behind motor decline is not clear. Motor slowing and parkinsonism have been shown to be related to periventricular white matter changes.34–36
There may also be a relationship between gait dysfunction and the presence of neurofibrillary tangles in the substantia nigra37
and markers of Alzheimer's disease pathology in the frontal lobes and basal ganglia.38, 39
Our study limitations include: The change point model requires large samples and long-term follow-up and may be difficult to generalize to individuals due to inter-individual variability. This model does not allow for time-varying covariates which limits the ability to assess the contributions of health conditions that develop during follow-up. We were unable to determine the upper confidence limits of the change point in gait speed for men and the combined analysis due to left censoring. This may be due to the need for a larger sample or longer follow-up. Additionally, the change point is calculated relative to the age of MCI onset and the use of alternate criteria to define the age of MCI onset could move the change point either earlier or later than the values reported here.
Despite these limitations, there are several strengths to our study. We used longitudinal data with up to 20 years of follow-up for some participants. Standardized, validated testing measures were used in the evaluations. Our participants were generally healthy with no major comorbid illnesses at baseline and a low rate of development of intercurrent illnesses, which were accounted for in subsequent analyses.
This study complements findings from other studies in this cohort showing accelerated cognitive decline on neuropsychological testing 3 to 4 years prior to MCI and accelerated expansion of ventricular volumes 2 years prior to the onset of MCI.23, 24
Future studies may compare these different methods for assessing disease progression to determine which is the more sensitive measure predicting the onset of cognitive impairment. The use of annual data may be complemented by use of more continuous, home-based gait monitoring. This allows for more frequent and ecologically representative assessment of gait speeds which suggest that there are differences in the variance of daily acquired gait speeds between MCI and normal subjects.40
These findings have important implications for identifying cognitive impairment at the earliest pre-clinical stages when initiation of disease-modifying therapies may be most beneficial.