September/October 2017

Alzheimer's Update: Predicting Dementia via Gait Slowing While Talking
By Manuel Montero-Odasso, MD, PhD, AGSF, FRCPC, and Yanina Sarquis-Adamson, PhD
Today's Geriatric Medicine
Vol. 10 No. 5 P. 32

Mild cognitive impairment (MCI) is considered a state between normal cognition and dementia that increases the risk of progressing to dementia by as much as tenfold.1 However, almost one-third of individuals remain stable after being diagnosed with MCI or even revert to normal cognitive functioning, highlighting the danger of considering all MCI patients as equal.2,3 These differences challenge clinical management once MCI is identified, as it is problematic to predict who will progress to dementia, including Alzheimer's disease (AD). To overcome this challenge, the identification of clinically useful and easy-to-use biomarkers of progression to dementia, including motor markers, is highly necessary in MCI.4-7

Although the main characteristic of MCI is memory impairment,8 problems with mobility and gait impairment have been previously described.8-10 Specifically, the authors' group has focused on dual-task gait testing (walking while simultaneously performing a challenging task, such as counting or naming objects) as a way to determine the risk of progression to dementia in people with MCI.11,12 Studies have shown that mobility and cognition are controlled by the same brain regions and networks,11,13-16 and this is the reason behind the challenges of the dual-task gait test.17-19

When people are asked to walk and perform a cognitive task at the same time, these regions of the brain become overloaded because they have to share the resources between the two tasks. In people who are cognitively impaired, these networks become increasingly overloaded due to having less cognitive reserve.11,16 Thus, the amount of gait slowing a person exhibits while performing a dual-task gait test, compared with his or her usual gait velocity (without a cognitive task) provides a measure of the person's deficits in executive function, attention, and memory processes.18,20-23 This magnitude of gait slowing can be expressed as a dual-task gait cost, which adjusts for the individual's own usual walking characteristics.24

Significant Study Findings
In our recent study, we examined the association of dual-task gait performance and the incidence of dementia in people with MCI. These participants were followed for six years as part of the Gait and Brain Study, an ongoing study (clinicaltrials.gov identifier: NTC03020381) designed to determine whether gait deficits can predict cognitive and mobility decline and progression to dementia among community-dwelling older adults.25

Participants in this study underwent an initial evaluation and then returned for subsequent assessments twice per week for a maximum of six years. All participants were community-living adults fulfilling MCI diagnostic criteria. Cognitive performance was assessed by using the Mini-Mental State Examination, the Montreal Cognitive Assessment, and the Clinical Dementia Rating (CDR) scale. Further neuropsychological tests were administered to help identify progression to dementia.26-29

Gait velocity under single and dual tasks was evaluated using an electronic mat (GAITRite System, 600 cm long and 64 cm wide) which provides data from both spatial and temporal gait parameters.30 First, participants were asked to walk on the mat at their usual pace in a quiet, well-lit room wearing comfortable footwear and without the use of any mobility aids. For the dual-task tests, participants walked at their usual pace while performing the following cognitive tasks aloud: counting backward from 100 by ones, subtracting serial sevens from 100, and naming animals. We then determined the burden of the cognitive challenge on gait performance by calculating the dual-task gait cost (%), using the equation ([usual gait velocity – dual-task gait velocity] / usual gait velocity) X 100.17,25

The main outcome we were evaluating was progression to dementia, and this was determined by a clinician investigator during follow-up visits according to Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision criteria31 and when the CDR test increased to a score of one or higher.

Gait velocity and dual-task gait cost were the variables selected to test for their ability to predict dementia; they were chosen because they have been previously associated with cognitive performance in MCI studies.12,25 Slow gait velocity in the usual gait condition was defined as less than 0.8 m/s, a threshold previously established for predicting adverse events, including cognitive decline.32-34

We assessed 112 participants (average age 76; 49% women) with an average follow-up time of 24 months (range, 12 to 76 months). A total of 24% of the sample (27 participants, 43% women) progressed to dementia, among whom 23 participants (85%) progressed to AD, two (7%) to Lewy body dementia, one (4%) to fronto-temporal dementia, and one (4%) to vascular dementia.

We found that gait velocity and the prevalence of slow usual-gait velocity (<0.8 m/s) failed to predict progression to dementia. However, dual-task gait velocity and dual-task cost were both associated with dementia progression. Furthermore, the prevalence of a high dual-task cost (slowing down more than 20% while dual tasking) also increased the risk of progressing to dementia. The dual tasks with a best predictive ability were counting backwards and naming animals.

Predictive Dual-Task Gait Testing
Thus, our results suggest that dual-task gait testing can predict the progression to dementia in older adults with MCI. Specifically, a high dual-task gait cost while counting backwards and naming animals was associated with an increased risk of progression to dementia by almost four times. A gait velocity test is easy to perform and provides an excellent general measure of overall function. However, dual-task gait testing can uncover valuable details regarding the role of cognitive control on a participant's gait.32,35-38

Whether dual-task changes in gait in MCI patients is associated with progression to vascular dementia or AD is unknown. Previous studies in general populations have suggested that gait slowing during dual tasking is most likely associated with incident vascular dementia.7,39 In the current study, dual-task gait change was associated mostly with AD; this can be explained by the fact that our study focused only on MCI individuals. Interestingly, emerging evidence is linking gait performance with AD neurodegenerative changes.40,41 Taken together, these data suggest that both vascular and neurodegenerative changes may contribute to dementia progression in MCI patients with impaired dual-task gait.42

The underlying mechanisms affecting dual-task gait performance remain not completely understood. What does seem clear is that the energetic demands used for gait and for the selected cognitive tasks may share a similar pathogenic mechanism at the brain level.25,43,44 Episodic memory, a cognitive domain that was affected in all of our participants who progressed to dementia, relies on frontal-hippocampal circuits that are also central for gait control. In addition, gait control relies on the prefrontal-striatal networks that are involved in executive function, which was similarly impaired in all of our participants who progressed to dementia.45

Prior imaging brain studies in MCI revealed that higher dual-task gait cost is associated with altered neurochemistry and low volume of the primary motor cortex, which is part of the executive network circuit of normal locomotion.15,46,47 Ultimately these brain circuits shared by both cognition and motor-gait performance can be affected by aging, neurodegenerative, and microvascular mechanisms, providing a foundation to propose that dual-task gait testing may serve as a "brain stress test" to detect future cognitive decline in individuals with undetected damage.48

Current dementia biomarkers, including amyloid-beta and tau protein-related markers, are promising; however, the correlation between the biomarkers' presence and actual dementia status decreases with age.19,49 In other words, older MCI patients with similar degrees of neuropathology burden may present different clinical states as they age. This warrants the need to expand the prediction of dementia progression by adding "functional markers," such as the dual-task gait test, which aims to evaluate the motor-cognitive interface.19

Our findings could be easily translated to the clinical setting in light of the simplicity, noninvasive nature, and low cost of dual-task gait assessment. Our sensitivity analysis showed that dual-task gait was comparable to cognitive testing to predict incident dementia. Performances in the three dual tasks used were all associated with a high risk of progression to dementia, providing flexibility to clinicians to choose the most appropriate dual-task test to cognitively stress a given patient.

Clinicians may utilize dual-task gait testing in screening patients with MCI who could benefit the most from additional testing, optimizing recommendations for imaging, spinal fluid exams, and genetic testing. Similarly, our findings can assist to identify high-risk individuals with MCI to plan the frequency of follow-up visits to monitor function. Finally, dual-task gait testing could help researchers plan primary prevention or intervention studies in MCI through the selection of subjects at greater risk of decline and progression to dementia.

In conclusion, dual-task gait testing can detect individuals with MCI at increased risk of progression to dementia. Our results support the hypothesis that cognitive and motor dysfunction in MCI may reflect a shared pathogenic mechanism at the brain level and that gait is a candidate motor biomarker of progression to dementia.11,14,25,50,51

— Manuel Montero-Odasso, MD, PhD, AGSF, FRCPC, is a professor of medicine, epidemiology, and biostatistics at the University of Western Ontario in Canada and director of the Gait and Brain Lab at Parkwood Institute in London, Ontario, Canada. An internist, geriatrician, and clinician scientist with a research focus on the relationship between mobility and cognitive problems in older adults, he focuses on gait performance research as methodology to early detection and future prevention of frailty, falls, and dementia in older people. He is a team leader in the Canadian Consortium on Neurodegeneration in Aging, Canada's dementia research strategy.

— Yanina Sarquis-Adamson, PhD, is research coordinator at the Gait and Brain Lab at Parkwood Institute in London, Ontario, Canada. She assists with the projects being conducted at the lab, using motor biomarkers such as slowing gait and dual-task gait to predict progression to dementia.

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