This study shows that impaired neurovascular coupling is associated with slow gait in elderly people with WMH. While those individuals with a high burden of WMH were more likely to be slow walkers, the likelihood of being a slow walker was more than twice as high if neurovascular coupling was also impaired.
Given that both impaired cerebral vasoreactivity and slow gait speed are associated with WMH, which likely results from long standing cerebral vasculopathy and ischemic injury, we initially hypothesized that WMH would also be associated with impaired neurovascular coupling. However, we did not see this relationship. Individuals who could activate their blood flow effectively were able to maintain a fast speed despite a high burden of WMH. Therefore, neurovascular coupling may be a compensatory mechanism that serves to maintain functional performance in the face of structural brain lesions.
Very few studies of neurovascular coupling have been conducted in humans. In one study, impaired neurovascular coupling was associated with untreated hypertension. The effect of hypertension was studied in 37 untreated hypertensive subjects and 59 normotensive control subjects during the performance of two memory and one sensorimotor tasks. Global and regional cerebral blood flow was assessed with positive emission tomography (PET). Regional cerebral blood flow responses to the tasks were blunted in the hypertensives, particularly in parietal cortex34
. However, we did not find a significant relationship between treated hypertension and neurovascular coupling.
The effect of aging on neurovascular coupling is less clear. Despite age related changes in vascular structure, cerebral blood flow regulation has not been shown to be altered in human aging.35, 36
In one study of 20 healthy volunteers 10–60 years old without vascular disease, blood flow activation during a visual stimulation paradigm was similar across all age groups37
. However, in another study, prefrontal neurovascular coupling was attenuated in older individuals.38
We have previously shown a tendency for elderly subjects to have greater and more generalized increases in anterior and posterior cerebral artery blood flow velocities than young subjects during word-stem completion and visual tasks.39
In animal studies, aging has been shown to be associated with impaired neurovascular coupling.40
In our study, across a limited, older age range, age was associated with impaired neurovascular coupling only in the left MCA.
The lack of a stronger relationship between neurovascular coupling and hypertension or age in our cohort may be related to at least two issues. The first may be a power issue. All prior studies of neurovascular coupling, including our own study, included a relatively small sample size. A second critical factor to consider is cerebral vasoreactivity. Since hypertension and aging are both associated with reduced cerebral vasoreactivity36
and this variable was not controlled for in all the other studies of neurovascular coupling, the confounding effect of vasoreactivity on the findings from prior studies can not be excluded. Vasoreactivity was impaired to the same extent for all the participants in our study. This characteristic of our cohort could have reduced the effects of age and hypertension on neurovascular coupling. Future longitudinal studies designed to explore these mechanistic pathways are needed.
We chose an executive function task for assessing the relation between neurovascular coupling and gait speed, rather than a motor task, because executive function is strongly related to gait speed41
, and we could not obtain reliable TCD recordings during motor activity. Future studies should determine if blood flow changes are similar across different tasks and vascular territories or if they are task and territory specific.
In summary, we showed that neurovascular coupling was attenuated in subjects with slow gait speed. Intact neurovascular regulatory mechanisms were associated with fast gait speed even in individuals with a high burden of WMH. Neurovascular coupling may be involved in compensatory mechanisms responsible for preservation of gait speed in elderly people with vascular disease and as such may prove to be a valuable therapeutic target in cerebrovascular disorders.