Neurovascular coupling: Key to gait slowing in aging?

Slowing of gait is ubiquitous with aging, 1–3 and mostly reflects disease effects on the neural pathways linking the cortical motor control areas to the peripheral effector organs like muscles and nerves. Clinical gait abnormalities of varying severity are present in almost one-third of community residing older adults. Neurological diseases such as strokes, Parkinson’s disease, or peripheral neuropathy account almost one-half of clinically diagnosed gait abnormalities in older adults. Gait dysfunction in older persons, whether diagnosed by clinicians or manifesting as slowing of gait, are major contributors to falls, can lead to activity restriction, and are associated with increased risk of institutionalization and death. While clinical gait evaluation is a standard part of the neurological examination and an essential component of fall risk assessments, very little research on gait changes in aging from a neurological perspective has been done. Abnormal cerebrovascular hemodynamics and the presence of cerebrovascular disease in older adults have been suggested to be important links between gait disturbances and adverse events such as falls. Impaired cerebral blood flow regulation has been linked to slow gait in older adults. Cerebral white matter hyperintensities (WMH) are associated not only with cerebral vascular dysregulation but also with slow gait in aging. The cerebral vasculature is endowed with neurovascular control mechanisms that assure the blood supply of the brain is commensurate to the energy needs of its cellular constituents. It has been known for over a century that brain activity can increase local cerebral blood flow. Neurovascular coupling (NVC) refers to the relationship between local neural activity and subsequent changes in local cerebral blood flow. The magnitude and spatial location of blood flow changes are linked to changes in neural activity through a complex sequence of coordinated events involving neurons, glia, and vascular cells. Many vascular-based functional brain imaging techniques, such as functional magnetic resonance imaging, rely on this coupling to infer changes in neural activity. Cerebral blood flow or metabolic changes during various activities is used as a proxy for NVC in these methods. NVC is disrupted in many pathological conditions, such as hypertension, Alzheimer’s disease, and ischemic strokes. NVC might, hence, be an important mechanism mediating the association between cerebrovascular disease and gait disturbances in aging. In this issue of Annals of Neurology, Sorond and colleagues investigated the association between NVC and gait in older individuals with cerebral vascular dysregulation (as measured by cerebral vasoreactivity to hypercapnia using transcranial Doppler ultrasound probes). The investigators hypothesized that NVC would be attenuated in slow walkers and would be associated with the presence of WMH on neuroimaging. They enrolled 22 fast walkers ( 0.67m/sec) and 20 slow walkers (<0.67m/sec) in the lowest quartile of cerebral vasoreactivity selected from a cohort of 765 community-dwelling older adults participating in the MOBILIZE Boston study. Transcranial Doppler ultrasound measurements of blood flow in both middle cerebral arteries were done during a control condition (identify the letter ‘‘x’’ from a series of letters shown on a computer screen) and the N-back test, a continuous working memory task designed to stimulate brain activity. NVC was operationally defined in this study as the mean percent change in blood flow volume in the middle cerebral arteries during the N-back test compared to blood flow during the control task. Cerebral WMH identified on magnetic resonance imaging in study participants was categorized into high or low burden based on the distribution above and below the median value for the sample. The main finding of this study was that NVC was lower in slow walkers compared to fast walkers (2.8% vs 8.2%). While the presence of high WMH burden was associated with slow walking (odds ratio 1⁄4 6.4), the risk of belonging to the slow walker group was more than doubled (odds ratio 1⁄4 14.5) if NVC was also impaired. This is the first study to examine the relationship of gait speed to NVC and, despite the small sample size, provides insights into causes of slowing of gait seen with aging. There are several reports of reduced cerebral vasoreactivity to hypercapnia in older adults, indicating an impaired vasodilatative capacity of cortical arterioles. But such findings do not imply an impairment of NVC since the mechanisms engaged in vasodilation to hypercapnia or in response to cortical activation to cognitive or motor tasks may be different. It might make sense that cerebral vascular dysregulation would be associated with both high WMH burden and decreased NVC, and