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Gait and dementia
Handbook of Clinical Neurology, Vol. 167 (3rd series) Geriatric Neurology S.T. DeKosky and S. Asthana, Editors https://doi.org/10.1016/B978-0-12-804766-8.00022-4 Copyright © 2019 Elsevier B.V. All rights reserved
Chapter 22
Gait and dementia JASON A. COHEN1 AND JOE VERGHESE1,2* Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, United States
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Departments of Neurology and Medicine, Albert Einstein College of Medicine, Bronx, NY, United States
Abstract Cognitive decline and neurodegenerative disease have been implicated in gait dysfunction via disturbance of top-down control mechanisms. Gait velocity decreases, variability increases, and ability to multitask while walking is impaired as cognition declines. Changes in gait can be used to predict incident mild cognitive impairment states as well as dementia. Slow gait velocity together with a cognitive complaint, the Motoric Cognitive Risk syndrome, can serve as a clinical biomarker for high risk of neurologic decline. While patients with Alzheimer’s disease typically have quantitative gait impairment, those with other forms of dementia often manifest more overt, qualitative changes to walking. A variety of interventions may be useful to improve gait, including physical and cognitive rehabilitation, treatment of specific underlying causes of gait problems, and treatment of the dementia itself. Understanding the relationship between gait and dementia can elucidate pathology and improve patient care.
INTRODUCTION The ability to ambulate independently is a major contributor to overall well-being and autonomy in older individuals. Increasing our understanding of gait and its decline is crucial to maximize health and function in older patients. Gait disturbances are common in aging. Abnormal gaits were diagnosed by clinicians in 35% of older adults in an urban community-based cohort study (Verghese et al., 2006). Those with abnormal gaits in this cohort had over twice the risk of death or institutionalization over 5 years of follow-up (Verghese et al., 2006), confirming the importance of identifying gait disturbances in older patients. Difficulty in walking increases with advancing age; the incidence of abnormal gait was reported to be 168.6 cases per 1000 person-years, and increased with age (Verghese et al., 2006). In another community-based study, the prevalence of self-reported difficulty in walking increased by decade, with more than half of those over age 80 reporting limitations in walking (Ostchega et al., 2000). The fluidity of movement during walking is due to the coordination of neural activity in the spinal cord,
brainstem, cerebellum, and cerebrum. Top-down control and coordination of walking have been examined using a variety of different methods, and have been shown to reside in the brain stem, primary motor cortex, premotor cortex, supplementary motor area, and other gray matter structures (e.g., Kapreli et al., 2007; Wang et al., 2008; Wieser et al., 2010; Koenraadt et al., 2014). Aside from brain regions that are more specific for motor movement and planning, areas such as the prefrontal cortex are increasingly implicated in higher level control of gait. The prefrontal cortex activates while walking, in particular, with more challenging locomotion activities such as walking while performing a concurrent task (“dual-task” walking) (Holtzer et al., 2011, 2015). Damage to the prefrontal cortex due to stroke or neurodegenerative disease is associated with gait impairment, especially complex tasks such as dual-task walking (e.g., Al-Yahya et al., 2016; Maidan et al., 2016). Enhancing brain activation at the prefrontal cortex, in both normal adults (Zhou et al., 2014; Wrightson et al., 2015) and those with brain diseases (Yip et al., 2013; Valentino et al., 2014; Burhan et al., 2015; Kim et al., 2015) with transcranial magnetic
*Correspondence to: Joe Verghese, M.B.B.S., M.S., 1225 Morris Park Avenue, Van Etten Room 308, Albert Einstein College of Medicine, Bronx, NY 10461, United States. Tel: +1-718-430-3877, Fax: +1-718-430-3870, E-mail: [email protected]
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or direct current stimulation is being explored as an exciting new strategy to improve gait performance. The breakdown of gait independence in older adults can be due to age-associated changes or could represent the effects of true pathology on structures involved in locomotion. Risk factors for gait abnormalities include age-related and pathologic changes to the central and peripheral nervous system, musculoskeletal system, and various other health factors. The role of cognitive decline in gait dysfunction has only been elucidated more recently. Herein, we review changes in gait with normal aging and with cognitive decline, gait assessment methods in older patients, specific changes in gait associated with Alzheimer’s disease (AD) and other dementias, and interventions that may improve gait in older individuals with cognitive decline.
Changes in gait with aging Walking requires coordination and integration of various components of the neuroaxis and the musculoskeletal system. Changes to these systems with aging can affect gait even in the absence of pathology. One of the most significant changes in walking patterns with advancing age is a decline in gait velocity, which happens even in healthy older adults (Oh-Park et al., 2010). This decline in gait velocity occurs despite maintenance of cadence (steps per minute) primarily because of decreased step length, which may reflect an adaptation to promote a more stable gait pattern (Winter et al., 1990). As people age, double stance time, i.e., time with both feet touching the ground while walking, increases. This is a more stable position than having one foot in the air, but results in shorter step length (Winter et al., 1990). Arthritis, joint deformities, and other biomechanical changes also contribute to shortened strides and decreased velocity with age (Sudarsky, 1990). In the Health and Retirement study cohort, a nationally representative sample of US older adults, modifiable risk factors associated with incidence of slow gait velocity over 4 years of follow-up were physical inactivity, muscle weakness, pain, low vision, prior falls, obesity, and cognitive impairment (Verghese et al., 2016). Together, these seven risk factors accounted for 77% of the population developing incident slow gait in the Health and Retirement study (Verghese et al., 2016).
Gait assessment A comprehensive gait assessment includes obtaining a clinical history, conducting a clinical and neurologic examination, and observing walking patterns in normal and challenging conditions. Gait can be assessed in a variety of ways, from eliciting self-report of gait difficulties from patients and clinical observation of walking by clinicians to quantitative electronic gait measurement of
footfall patterns and functional brain imaging while walking or performing related mobility tasks. Combining multiple modes of gait assessment may be better than any one assessment method in isolation to identify pathology and predict risk of various geriatric outcomes (Allali et al., 2015).
Neurologic examination and clinical gait classification Elderly patients regularly present with complex gait disorders, with concurrent contributions from multiple causal factors. Systems that clinically classify gait either ascribe gait impairments to levels of dysfunction within the neuroaxis (Nutt et al., 1993) or by clinical features (Sudarsky, 1990; Verghese et al., 2002), though the preference in clinical settings is for the latter approach (Snijders et al., 2007). Disorders of gait may be classified based on the presence of specific clinical features as being due to nonneurologic and neurologic causes or a combination of both. Pathology at almost any location within the nervous system, central or peripheral, can result in neurologic gait abnormalities. Though nonneurologic causes have an impact on gait, not all gait classifications account for their influence. Herein, we focus on neurologic causes of gait impairment as they can serve as markers of neurodegenerative disease and also shed light on some underlying cognitive processes. Parkinsonian gait is characterized by a narrow base, short strides, stooped posture, and reduced arm swing. Turns are often “en bloc,” with rotation of the head, trunk, and pelvis starting at the same time and with little relative movement between the body segments (Minna et al., 2009). These turns often require many steps to complete. Parkinsonian gaits can feature episodic “festination” or progressive acceleration to maintain balance. Hemiparetic gait is characterized by asymmetric weakness and increased tone. Affected musculature is generally in a long-tract distribution, with preferential involvement of upper extremity extensors (e.g., triceps) and lower extremity flexors (e.g., hamstrings). It is often the result of vascular damage such as strokes to the corticospinal tract. Causes of frontal gait include normal pressure hydrocephalus and multiple strokes or extensive subcortical vascular changes. Gait may appear “magnetic” with difficulty lifting feet off the floor, and generally has a wide base. Ataxic gaits are wide based and unsteady. They may be due to sensory loss, in particular, loss of proprioceptive (joint position sense) feedback, or can be due to disorders of the cerebellum and its connections. Of note, the Parkinsonian syndromes with early falls may mimic
GAIT AND DEMENTIA ataxic gait as they can be wide based as well due to truncal instability. Individuals with neuropathic gait have unilateral or bilateral foot drop and may have a “stocking” pattern of sensory loss with absent deep tendon reflexes. Functional gait disorders may have features that include improvement with distraction, fluctuation, excessive slowness of movement or hesitation, a lack of injurious falls, and uneconomic movements that require greater energy, strength, or balance than would normal locomotion.
Quantitative gait assessment A detailed description of quantitative gait assessment methods is beyond the scope of this chapter. In general, quantitative approaches involve kinematic studies that analyze body movements or use instrumented walkways, which analyze footfall patterns. These quantitative approaches provide valuable insights into gait mechanisms and pathologic processes that can result in gait impairment. However, the requirement for specialized equipment largely restricts their role in assessment of patients in clinical arenas. Specific quantitative gait abnormalities such as slowing of gait velocity or stepto-step variability in step length are associated with prevalent cognitive impairment and incident cognitive decline, and are discussed in the following text. Measuring time taken to walk a fixed distance, on the other hand, can be done using a stopwatch and can be easily adopted in various clinical settings (Studenski et al., 2003). Timed gait has been used to define health states such as frailty (Fried et al., 2001), to predict outcomes such as falls (Verghese et al., 2009), and in defining predementia syndromes (Verghese et al., 2013a).
Changes in gait with cognitive impairment Control of gait occurs via multiple cognitive domains, most notably executive functions. Executive functions are the brain systems involved in working memory, selective maintenance of attention, reasoning, and cognitive integration, and largely localize to the prefrontal cortex. Executive functions are related to diverse gait parameters, including velocity (e.g., Holtzer et al., 2012; Martin et al., 2013; Killane et al., 2014; Best et al., 2015), step length (Martin et al., 2013), and timing of leg motion during the gait cycle (Martin et al., 2013). Decreased executive function is associated with increased variability of gait parameters while walking (Holtzer et al., 2012; Martin et al., 2013), a marker of impaired gait control. Executive function is also associated with functional gait outcomes, such as time to climb stairs or time to stand, walk, turn, and sit (Timed Up and Go) (Gothe et al., 2014). Prospectively, decline in
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executive functions over time is associated with decline in gait velocity, for both those with and without cognitive impairment at baseline (Callisaya et al., 2015). Improvement in executive functions over time is associated with improved gait speed (Best et al., 2015). Other cognitive domains also affect gait. Processing speed (Killane et al., 2014), verbal ability (Holtzer et al., 2012), and short-term memory (Holtzer et al., 2012; Mielke et al., 2013; Killane et al., 2014) have all been shown to be related to gait velocity. Beauchet et al. (2015) found that memory and executive function interact such that those with impairments in both domains had greater impairment of gait than would be predicted by summing the effects alone.
Gait and prediction of incident dementia In nondemented older adults, changes in gait parameters— in particular, slower gait velocity and increased variability in gait parameters—can predict decline in multiple cognitive domains (Beauchet et al., 2014a). Faster baseline gait is associated with less decline over time in global and several domain-specific cognitive measures (Mielke et al., 2013). Gait velocity is slower (Doi et al., 2015) and declines faster (Verghese et al., 2013b) in those with the apolipoprotein (APOE)-e4 genotype (a significant genetic risk factor for dementia) than those without this allele. Gait dysfunction due to neurologic causes predicts incident dementia and both all-cause (e.g., Verghese et al., 2002; van Kan et al., 2012) and vascular dementia (Verghese et al., 2002). Among older adults, the presence of any one of hemiparetic, ataxic, or frontal gait patterns (also termed as “high risk neurological syndrome”) was associated with more than a threefold increased risk of developing vascular dementia within 3 years (Verghese et al., 2007a). Patterns of quantitative gait impairment might also differentially predict Alzheimer’s vs vascular dementia (Verghese et al., 2007b).
Changes in gait with predementia syndromes Neurodegenerative changes occur on a spectrum (Sperling et al., 2011). Dementia, or major neurocognitive disorder, refers to a state of cognitive decline from a previously normal baseline that is sufficient to interfere with daily activities. Pathologic changes may start decades before diagnosis of dementia (e.g., Clifford et al., 2013), and cognition may decline for many years before criteria for dementia are met (e.g., AguirreAcevedo et al., 2016). During this long preclinical phase, changes in both cognitive and motoric (Buracchio et al., 2010) markers may be seen on examination of older patients.
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Mild cognitive impairment syndrome Mild cognitive impairment (MCI), or mild neurocognitive disorder, can be thought of as a predementia state in which there is decline in cognitive function from a previous cognitively normal baseline but not to the degree where daily activities are impaired. MCI can be divided into amnestic (aMCI; in which the primary domain affected is memory) and nonamnestic (naMCI; in which memory is relatively spared) forms. AD is presumed to be the pathologic basis of aMCI, whereas naMCI can be due to an array of non-Alzheimer pathologies. An estimated 5%–10% of those with MCI convert to dementia annually, with a relative risk (compared to older adults with normal cognition) of conversion of 8.9 for AD and 13.8 for dementia of any cause reported in a metaanalysis of 41 studies (Mitchell and Shiri-Feshki, 2009). Older adults with MCI have worse gait performance than older adults with normal cognition, but better performance than those with dementia (e.g., Borges et al., 2015). When the cognitive demands of walking are increased by performance of a concurrent task (i.e., a dual-task), the effect of cognitive status on gait is magnified (Muir et al., 2012; Borges et al., 2015). Among those with cognitive impairment, global measures of cognitive ability and also specific measures, such as those assessing executive functions, are related to multiple gait parameters (Bruce-Keller et al., 2012). While cognitive measures do not correlate with gait in normal older adults, artificially limiting the available cognitive resources by the use of a dual-task paradigm, essentially simulating MCI or dementia, can cause associations between gait parameters and cognitive function to emerge (Bruce-Keller et al., 2012). Depending on the pattern of cognitive impairment, differences in gait may be found. For instance, those with aMCI show increased gait variability (Beauchet et al., 2011a; Montero-Odasso et al., 2014) and increased difficulty with dual-task walking compared to normal gait relative to those with naMCI (Doi et al., 2014; Montero-Odasso et al., 2014). Other research has found that, even when the effects of dual-task walking are similar in the extent of slowing of gait in individuals with aMCI and naMCI, the brain structures that support dual-task locomotion differ between those with aMCI and those with naMCI (Doi et al., 2017). Spatial navigation and visuospatial abilities may also affect locomotion, and may result in wandering behaviors, which are common in dementia patients. These domains are classically affected early in the course of AD, and similar deficits have been found in MCI as well (Iachini et al., 2009). Those with aMCI have impaired ability to navigate a maze (Hort et al., 2007; Laczo et al., 2012), and their performance correlates with right
hippocampal volume (an early site of neurodegeneration in AD). Among those with aMCI, presence of the APOEe4 genotype is associated with relatively worse navigational abilities (Laczó et al., 2014).
MOTORIC COGNITIVE RISK SYNDROME Given the relationship between gait impairment and incident cognitive impairment, the role of gait as a clinical biomarker of presymptomatic neurodegenerative disease has been explored. The combination of slow gait and impairment on cognitive assessment predicts progression to dementia (Montero-Odasso et al., 2016). However, neuropsychologic assessment is time consuming, and may be biased by education, language, literacy levels, and culture. Verghese and colleagues proposed a Motoric Cognitive Risk (MCR) syndrome, defined as the presence of slow gait (one standard deviation below age- and sex-matched peers) and cognitive complaint (Verghese et al., 2013a), as a predementia syndrome that could be diagnosed without requiring cognitive tests or specialized equipment. MCR predicts all-cause dementia (Verghese et al., 2013a, 2014a), vascular dementia (Verghese et al., 2013a), and AD (Verghese et al., 2014a), and does so beyond the associations of slow gait or cognitive complaint alone. These findings hold even if those who meet criteria for both MCR and MCI are excluded or if those who develop dementia within the first few years after MCR diagnosis are excluded (Verghese et al., 2013a, 2014a). Pooled prevalence of MCR in over 26,000 older adults from 17 countries was 9.7% (Verghese et al., 2014a). The adjusted incidence of MCR in a pooled sample of older adults from different US studies was 65.2/1000 person-years, and incidence increased with age, obesity, depression, stroke, Parkinson’s disease (PD), and sedentariness (Verghese et al., 2014b). Other studies have indicated that MCR can also predict risk of falls (Callisaya et al., 2016) as well as mortality (Ayers and Verghese, 2015).
Gait disturbances in Alzheimer’s disease Gait disturbance is not traditionally considered a feature of AD. As described earlier, however, gait dysfunction predicts incident dementia and correlates with cognitive performance. Among patients with MCI, those who have gait, balance, and motor dysfunction have an increased risk of converting to AD (Aggarwal et al., 2006). As dementia progresses, changes to walking and other motoric abilities continue that eventually lead to loss of mobility and being bed bound (Scarmeas et al., 2004). These changes in walking and other motoric abilities predict further cognitive loss, functional decline, institutionalization, and death (Scarmeas et al., 2005).
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Gait disturbances in other dementias Other dementia syndromes are associated with specific and, at times, more overt patterns of gait dysfunction than in AD (Allan et al., 2005). Vascular cognitive impairment may commonly result in hemiparetic, frontal, or ataxic gaits. Idiopathic PD and Parkinson’s dementia typically feature classic Parkinsonian gaits. Progressive supranuclear palsy and vascular parkinsonism may have a wider base or a more “frontal” appearance, and may be associated with other neurologic abnormalities involving eye movements, balance, or limb positioning. Idiopathic normal pressure hydrocephalus is caused by the effects of increased cerebrospinal fluid on the brain parenchyma, particularly the frontal lobes. It results in a frontal pattern of gait dysfunction, cognitive decline, and urinary incontinence. Removal of a large volume of spinal fluid by lumbar puncture or lumbar drain can rapidly improve gait. Those with qualitatively (Mihalj et al., 2016) and quantitatively (Yang et al., 2016; Schniepp et al., 2017) improved gait after spinal fluid removal are likely to respond to definitive treatment, a ventricular shunt (Halperin et al., 2015). Lack of gait improvement does not necessarily indicate that patients will not respond to a shunt (Mihalj et al., 2016). While gait abnormalities have been described in those with frontotemporal dementia (e.g., Allali et al., 2010), they do not typically feature a frontal gait pattern. Frontotemporal dementia can cooccur with amyotrophic lateral sclerosis; depending on the pattern of upper- and lower-motor neuron involvement, a variety of gait patterns can be seen. Gait dysfunction in corticobasal degeneration is variable, and depends upon the limb(s) involved and the specific symptoms present, for instance dystonia or parkinsonism.
GAIT INTERVENTIONS A multidomain intervention strategy is required to treat gait disorders. The focus of treatment in individuals with gait and cognitive disorders is to identify and treat underlying causes including dementia, address mobility limitations through rehabilitation and other approaches, and prevent complications such as falls.
Rehabilitation and exercise Physical therapy can help strengthen weak muscles, improve balance, and teach compensatory gait strategies. An aerobic exercise regimen and a program aiming to improve fitness and tone both improved Timed Up and Go performance and time needed to climb stairs (Gothe et al., 2014). Complex motor tasks that have substantial cognitive components, such as dance, can improve physical function (e.g., Kattenstroth et al., 2013). Various types of dance have also been studied
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in PD, where it has been found to improve various aspects of gait dysfunction (Hackney and Earhart, 2009, 2010; Hackney et al., 2015). Both physiotherapy (Tomlinson et al., 2013) and aerobic exercise (Shu et al., 2014) have also been shown to improve gait in PD.
Cognitive training Exercise programs and physical therapy are beneficial, yet difficult for most people to maintain for prolonged time periods. They may also not be possible in those with significant pain, mobility limitations, or other significant medical comorbidities, who might benefit the most from improved walking. Therefore, training programs targeting the cognitive domains that subserve gait have been studied for their ability to improve walking in older adults. Cognitive training exercises, generally computer-based and without any motor component, can improve gait (Verghese et al., 2010; Smith-Ray et al., 2014) and balance (Li et al., 2010; SmithRay et al., 2014).
Medications Low vitamin D levels are associated with slower walking speed and worse strength (Wicherts et al., 2007; Mastaglia et al., 2011), worse balance (Wicherts et al., 2007), increased gait variability (Beauchet et al., 2011b), and increased decline in gait over time (Wicherts et al., 2007). Vitamin D supplementation may improve gait (Muir and Montero-Odasso, 2011), though it is unclear if supplementation reduces fall risk over time (BischoffFerrari et al., 2004; Michael et al., 2010; Murad et al., 2011; Gillespie et al., 2012). This benefit may be stronger in those with baseline vitamin D deficiency and those who receive vitamin D with calcium (Murad et al., 2011). Treatment of the underlying neurodegenerative disease may be effective in improving gait. In those with mild AD, cholinesterase inhibitors may improve gait velocity (Montero-Odasso et al., 2015), though the effects on improvement in gait variability are mixed (Beauchet et al., 2014b; Montero-Odasso et al., 2015). Both dopaminergic medications and deep brain stimulation can improve some aspects of gait in those with PD (McNeely and Earhart, 2013). In those with Huntington’s disease, treating chorea with tetrabenazine results in improvements in gait and balance (Kegelmeyer et al., 2014). In those with multiple sclerosis, dalfampridine may be used specifically to improve gait (Egeberg et al., 2012). Certain classes of medications may worsen gait, though more research is needed to clarify the underlying mechanisms (e.g., Donoghue et al., 2015; George and Verghese, 2016). Numerous medications, in particular sedatives and hypnotics, increase the risk of falls in older
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adults (Huang et al., 2012), though further discussion is beyond the scope of this chapter.
CONCLUSION There are strong relationships between gait and cognition. They can each be used to elucidate the underlying physiology of the other. Changes in gait can be used as clinical markers of nervous system pathology, allowing for earlier identification of neurodegenerative disease. Gait dysfunction is common in neurodegenerative disease and dementia, and a crucial part of managing people with dementia is assessment of gait. Treatment of dementia can improve gait. Learning more about these relationships will hopefully allow continued improvement in patient care.
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Chapter 22
Gait and dementia JASON A. COHEN1 AND JOE VERGHESE1,2* Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, United States
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Departments of Neurology and Medicine, Albert Einstein College of Medicine, Bronx, NY, United States
Abstract Cognitive decline and neurodegenerative disease have been implicated in gait dysfunction via disturbance of top-down control mechanisms. Gait velocity decreases, variability increases, and ability to multitask while walking is impaired as cognition declines. Changes in gait can be used to predict incident mild cognitive impairment states as well as dementia. Slow gait velocity together with a cognitive complaint, the Motoric Cognitive Risk syndrome, can serve as a clinical biomarker for high risk of neurologic decline. While patients with Alzheimer’s disease typically have quantitative gait impairment, those with other forms of dementia often manifest more overt, qualitative changes to walking. A variety of interventions may be useful to improve gait, including physical and cognitive rehabilitation, treatment of specific underlying causes of gait problems, and treatment of the dementia itself. Understanding the relationship between gait and dementia can elucidate pathology and improve patient care.
INTRODUCTION The ability to ambulate independently is a major contributor to overall well-being and autonomy in older individuals. Increasing our understanding of gait and its decline is crucial to maximize health and function in older patients. Gait disturbances are common in aging. Abnormal gaits were diagnosed by clinicians in 35% of older adults in an urban community-based cohort study (Verghese et al., 2006). Those with abnormal gaits in this cohort had over twice the risk of death or institutionalization over 5 years of follow-up (Verghese et al., 2006), confirming the importance of identifying gait disturbances in older patients. Difficulty in walking increases with advancing age; the incidence of abnormal gait was reported to be 168.6 cases per 1000 person-years, and increased with age (Verghese et al., 2006). In another community-based study, the prevalence of self-reported difficulty in walking increased by decade, with more than half of those over age 80 reporting limitations in walking (Ostchega et al., 2000). The fluidity of movement during walking is due to the coordination of neural activity in the spinal cord,
brainstem, cerebellum, and cerebrum. Top-down control and coordination of walking have been examined using a variety of different methods, and have been shown to reside in the brain stem, primary motor cortex, premotor cortex, supplementary motor area, and other gray matter structures (e.g., Kapreli et al., 2007; Wang et al., 2008; Wieser et al., 2010; Koenraadt et al., 2014). Aside from brain regions that are more specific for motor movement and planning, areas such as the prefrontal cortex are increasingly implicated in higher level control of gait. The prefrontal cortex activates while walking, in particular, with more challenging locomotion activities such as walking while performing a concurrent task (“dual-task” walking) (Holtzer et al., 2011, 2015). Damage to the prefrontal cortex due to stroke or neurodegenerative disease is associated with gait impairment, especially complex tasks such as dual-task walking (e.g., Al-Yahya et al., 2016; Maidan et al., 2016). Enhancing brain activation at the prefrontal cortex, in both normal adults (Zhou et al., 2014; Wrightson et al., 2015) and those with brain diseases (Yip et al., 2013; Valentino et al., 2014; Burhan et al., 2015; Kim et al., 2015) with transcranial magnetic
*Correspondence to: Joe Verghese, M.B.B.S., M.S., 1225 Morris Park Avenue, Van Etten Room 308, Albert Einstein College of Medicine, Bronx, NY 10461, United States. Tel: +1-718-430-3877, Fax: +1-718-430-3870, E-mail: [email protected]
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or direct current stimulation is being explored as an exciting new strategy to improve gait performance. The breakdown of gait independence in older adults can be due to age-associated changes or could represent the effects of true pathology on structures involved in locomotion. Risk factors for gait abnormalities include age-related and pathologic changes to the central and peripheral nervous system, musculoskeletal system, and various other health factors. The role of cognitive decline in gait dysfunction has only been elucidated more recently. Herein, we review changes in gait with normal aging and with cognitive decline, gait assessment methods in older patients, specific changes in gait associated with Alzheimer’s disease (AD) and other dementias, and interventions that may improve gait in older individuals with cognitive decline.
Changes in gait with aging Walking requires coordination and integration of various components of the neuroaxis and the musculoskeletal system. Changes to these systems with aging can affect gait even in the absence of pathology. One of the most significant changes in walking patterns with advancing age is a decline in gait velocity, which happens even in healthy older adults (Oh-Park et al., 2010). This decline in gait velocity occurs despite maintenance of cadence (steps per minute) primarily because of decreased step length, which may reflect an adaptation to promote a more stable gait pattern (Winter et al., 1990). As people age, double stance time, i.e., time with both feet touching the ground while walking, increases. This is a more stable position than having one foot in the air, but results in shorter step length (Winter et al., 1990). Arthritis, joint deformities, and other biomechanical changes also contribute to shortened strides and decreased velocity with age (Sudarsky, 1990). In the Health and Retirement study cohort, a nationally representative sample of US older adults, modifiable risk factors associated with incidence of slow gait velocity over 4 years of follow-up were physical inactivity, muscle weakness, pain, low vision, prior falls, obesity, and cognitive impairment (Verghese et al., 2016). Together, these seven risk factors accounted for 77% of the population developing incident slow gait in the Health and Retirement study (Verghese et al., 2016).
Gait assessment A comprehensive gait assessment includes obtaining a clinical history, conducting a clinical and neurologic examination, and observing walking patterns in normal and challenging conditions. Gait can be assessed in a variety of ways, from eliciting self-report of gait difficulties from patients and clinical observation of walking by clinicians to quantitative electronic gait measurement of
footfall patterns and functional brain imaging while walking or performing related mobility tasks. Combining multiple modes of gait assessment may be better than any one assessment method in isolation to identify pathology and predict risk of various geriatric outcomes (Allali et al., 2015).
Neurologic examination and clinical gait classification Elderly patients regularly present with complex gait disorders, with concurrent contributions from multiple causal factors. Systems that clinically classify gait either ascribe gait impairments to levels of dysfunction within the neuroaxis (Nutt et al., 1993) or by clinical features (Sudarsky, 1990; Verghese et al., 2002), though the preference in clinical settings is for the latter approach (Snijders et al., 2007). Disorders of gait may be classified based on the presence of specific clinical features as being due to nonneurologic and neurologic causes or a combination of both. Pathology at almost any location within the nervous system, central or peripheral, can result in neurologic gait abnormalities. Though nonneurologic causes have an impact on gait, not all gait classifications account for their influence. Herein, we focus on neurologic causes of gait impairment as they can serve as markers of neurodegenerative disease and also shed light on some underlying cognitive processes. Parkinsonian gait is characterized by a narrow base, short strides, stooped posture, and reduced arm swing. Turns are often “en bloc,” with rotation of the head, trunk, and pelvis starting at the same time and with little relative movement between the body segments (Minna et al., 2009). These turns often require many steps to complete. Parkinsonian gaits can feature episodic “festination” or progressive acceleration to maintain balance. Hemiparetic gait is characterized by asymmetric weakness and increased tone. Affected musculature is generally in a long-tract distribution, with preferential involvement of upper extremity extensors (e.g., triceps) and lower extremity flexors (e.g., hamstrings). It is often the result of vascular damage such as strokes to the corticospinal tract. Causes of frontal gait include normal pressure hydrocephalus and multiple strokes or extensive subcortical vascular changes. Gait may appear “magnetic” with difficulty lifting feet off the floor, and generally has a wide base. Ataxic gaits are wide based and unsteady. They may be due to sensory loss, in particular, loss of proprioceptive (joint position sense) feedback, or can be due to disorders of the cerebellum and its connections. Of note, the Parkinsonian syndromes with early falls may mimic
GAIT AND DEMENTIA ataxic gait as they can be wide based as well due to truncal instability. Individuals with neuropathic gait have unilateral or bilateral foot drop and may have a “stocking” pattern of sensory loss with absent deep tendon reflexes. Functional gait disorders may have features that include improvement with distraction, fluctuation, excessive slowness of movement or hesitation, a lack of injurious falls, and uneconomic movements that require greater energy, strength, or balance than would normal locomotion.
Quantitative gait assessment A detailed description of quantitative gait assessment methods is beyond the scope of this chapter. In general, quantitative approaches involve kinematic studies that analyze body movements or use instrumented walkways, which analyze footfall patterns. These quantitative approaches provide valuable insights into gait mechanisms and pathologic processes that can result in gait impairment. However, the requirement for specialized equipment largely restricts their role in assessment of patients in clinical arenas. Specific quantitative gait abnormalities such as slowing of gait velocity or stepto-step variability in step length are associated with prevalent cognitive impairment and incident cognitive decline, and are discussed in the following text. Measuring time taken to walk a fixed distance, on the other hand, can be done using a stopwatch and can be easily adopted in various clinical settings (Studenski et al., 2003). Timed gait has been used to define health states such as frailty (Fried et al., 2001), to predict outcomes such as falls (Verghese et al., 2009), and in defining predementia syndromes (Verghese et al., 2013a).
Changes in gait with cognitive impairment Control of gait occurs via multiple cognitive domains, most notably executive functions. Executive functions are the brain systems involved in working memory, selective maintenance of attention, reasoning, and cognitive integration, and largely localize to the prefrontal cortex. Executive functions are related to diverse gait parameters, including velocity (e.g., Holtzer et al., 2012; Martin et al., 2013; Killane et al., 2014; Best et al., 2015), step length (Martin et al., 2013), and timing of leg motion during the gait cycle (Martin et al., 2013). Decreased executive function is associated with increased variability of gait parameters while walking (Holtzer et al., 2012; Martin et al., 2013), a marker of impaired gait control. Executive function is also associated with functional gait outcomes, such as time to climb stairs or time to stand, walk, turn, and sit (Timed Up and Go) (Gothe et al., 2014). Prospectively, decline in
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executive functions over time is associated with decline in gait velocity, for both those with and without cognitive impairment at baseline (Callisaya et al., 2015). Improvement in executive functions over time is associated with improved gait speed (Best et al., 2015). Other cognitive domains also affect gait. Processing speed (Killane et al., 2014), verbal ability (Holtzer et al., 2012), and short-term memory (Holtzer et al., 2012; Mielke et al., 2013; Killane et al., 2014) have all been shown to be related to gait velocity. Beauchet et al. (2015) found that memory and executive function interact such that those with impairments in both domains had greater impairment of gait than would be predicted by summing the effects alone.
Gait and prediction of incident dementia In nondemented older adults, changes in gait parameters— in particular, slower gait velocity and increased variability in gait parameters—can predict decline in multiple cognitive domains (Beauchet et al., 2014a). Faster baseline gait is associated with less decline over time in global and several domain-specific cognitive measures (Mielke et al., 2013). Gait velocity is slower (Doi et al., 2015) and declines faster (Verghese et al., 2013b) in those with the apolipoprotein (APOE)-e4 genotype (a significant genetic risk factor for dementia) than those without this allele. Gait dysfunction due to neurologic causes predicts incident dementia and both all-cause (e.g., Verghese et al., 2002; van Kan et al., 2012) and vascular dementia (Verghese et al., 2002). Among older adults, the presence of any one of hemiparetic, ataxic, or frontal gait patterns (also termed as “high risk neurological syndrome”) was associated with more than a threefold increased risk of developing vascular dementia within 3 years (Verghese et al., 2007a). Patterns of quantitative gait impairment might also differentially predict Alzheimer’s vs vascular dementia (Verghese et al., 2007b).
Changes in gait with predementia syndromes Neurodegenerative changes occur on a spectrum (Sperling et al., 2011). Dementia, or major neurocognitive disorder, refers to a state of cognitive decline from a previously normal baseline that is sufficient to interfere with daily activities. Pathologic changes may start decades before diagnosis of dementia (e.g., Clifford et al., 2013), and cognition may decline for many years before criteria for dementia are met (e.g., AguirreAcevedo et al., 2016). During this long preclinical phase, changes in both cognitive and motoric (Buracchio et al., 2010) markers may be seen on examination of older patients.
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Mild cognitive impairment syndrome Mild cognitive impairment (MCI), or mild neurocognitive disorder, can be thought of as a predementia state in which there is decline in cognitive function from a previous cognitively normal baseline but not to the degree where daily activities are impaired. MCI can be divided into amnestic (aMCI; in which the primary domain affected is memory) and nonamnestic (naMCI; in which memory is relatively spared) forms. AD is presumed to be the pathologic basis of aMCI, whereas naMCI can be due to an array of non-Alzheimer pathologies. An estimated 5%–10% of those with MCI convert to dementia annually, with a relative risk (compared to older adults with normal cognition) of conversion of 8.9 for AD and 13.8 for dementia of any cause reported in a metaanalysis of 41 studies (Mitchell and Shiri-Feshki, 2009). Older adults with MCI have worse gait performance than older adults with normal cognition, but better performance than those with dementia (e.g., Borges et al., 2015). When the cognitive demands of walking are increased by performance of a concurrent task (i.e., a dual-task), the effect of cognitive status on gait is magnified (Muir et al., 2012; Borges et al., 2015). Among those with cognitive impairment, global measures of cognitive ability and also specific measures, such as those assessing executive functions, are related to multiple gait parameters (Bruce-Keller et al., 2012). While cognitive measures do not correlate with gait in normal older adults, artificially limiting the available cognitive resources by the use of a dual-task paradigm, essentially simulating MCI or dementia, can cause associations between gait parameters and cognitive function to emerge (Bruce-Keller et al., 2012). Depending on the pattern of cognitive impairment, differences in gait may be found. For instance, those with aMCI show increased gait variability (Beauchet et al., 2011a; Montero-Odasso et al., 2014) and increased difficulty with dual-task walking compared to normal gait relative to those with naMCI (Doi et al., 2014; Montero-Odasso et al., 2014). Other research has found that, even when the effects of dual-task walking are similar in the extent of slowing of gait in individuals with aMCI and naMCI, the brain structures that support dual-task locomotion differ between those with aMCI and those with naMCI (Doi et al., 2017). Spatial navigation and visuospatial abilities may also affect locomotion, and may result in wandering behaviors, which are common in dementia patients. These domains are classically affected early in the course of AD, and similar deficits have been found in MCI as well (Iachini et al., 2009). Those with aMCI have impaired ability to navigate a maze (Hort et al., 2007; Laczo et al., 2012), and their performance correlates with right
hippocampal volume (an early site of neurodegeneration in AD). Among those with aMCI, presence of the APOEe4 genotype is associated with relatively worse navigational abilities (Laczó et al., 2014).
MOTORIC COGNITIVE RISK SYNDROME Given the relationship between gait impairment and incident cognitive impairment, the role of gait as a clinical biomarker of presymptomatic neurodegenerative disease has been explored. The combination of slow gait and impairment on cognitive assessment predicts progression to dementia (Montero-Odasso et al., 2016). However, neuropsychologic assessment is time consuming, and may be biased by education, language, literacy levels, and culture. Verghese and colleagues proposed a Motoric Cognitive Risk (MCR) syndrome, defined as the presence of slow gait (one standard deviation below age- and sex-matched peers) and cognitive complaint (Verghese et al., 2013a), as a predementia syndrome that could be diagnosed without requiring cognitive tests or specialized equipment. MCR predicts all-cause dementia (Verghese et al., 2013a, 2014a), vascular dementia (Verghese et al., 2013a), and AD (Verghese et al., 2014a), and does so beyond the associations of slow gait or cognitive complaint alone. These findings hold even if those who meet criteria for both MCR and MCI are excluded or if those who develop dementia within the first few years after MCR diagnosis are excluded (Verghese et al., 2013a, 2014a). Pooled prevalence of MCR in over 26,000 older adults from 17 countries was 9.7% (Verghese et al., 2014a). The adjusted incidence of MCR in a pooled sample of older adults from different US studies was 65.2/1000 person-years, and incidence increased with age, obesity, depression, stroke, Parkinson’s disease (PD), and sedentariness (Verghese et al., 2014b). Other studies have indicated that MCR can also predict risk of falls (Callisaya et al., 2016) as well as mortality (Ayers and Verghese, 2015).
Gait disturbances in Alzheimer’s disease Gait disturbance is not traditionally considered a feature of AD. As described earlier, however, gait dysfunction predicts incident dementia and correlates with cognitive performance. Among patients with MCI, those who have gait, balance, and motor dysfunction have an increased risk of converting to AD (Aggarwal et al., 2006). As dementia progresses, changes to walking and other motoric abilities continue that eventually lead to loss of mobility and being bed bound (Scarmeas et al., 2004). These changes in walking and other motoric abilities predict further cognitive loss, functional decline, institutionalization, and death (Scarmeas et al., 2005).
GAIT AND DEMENTIA
Gait disturbances in other dementias Other dementia syndromes are associated with specific and, at times, more overt patterns of gait dysfunction than in AD (Allan et al., 2005). Vascular cognitive impairment may commonly result in hemiparetic, frontal, or ataxic gaits. Idiopathic PD and Parkinson’s dementia typically feature classic Parkinsonian gaits. Progressive supranuclear palsy and vascular parkinsonism may have a wider base or a more “frontal” appearance, and may be associated with other neurologic abnormalities involving eye movements, balance, or limb positioning. Idiopathic normal pressure hydrocephalus is caused by the effects of increased cerebrospinal fluid on the brain parenchyma, particularly the frontal lobes. It results in a frontal pattern of gait dysfunction, cognitive decline, and urinary incontinence. Removal of a large volume of spinal fluid by lumbar puncture or lumbar drain can rapidly improve gait. Those with qualitatively (Mihalj et al., 2016) and quantitatively (Yang et al., 2016; Schniepp et al., 2017) improved gait after spinal fluid removal are likely to respond to definitive treatment, a ventricular shunt (Halperin et al., 2015). Lack of gait improvement does not necessarily indicate that patients will not respond to a shunt (Mihalj et al., 2016). While gait abnormalities have been described in those with frontotemporal dementia (e.g., Allali et al., 2010), they do not typically feature a frontal gait pattern. Frontotemporal dementia can cooccur with amyotrophic lateral sclerosis; depending on the pattern of upper- and lower-motor neuron involvement, a variety of gait patterns can be seen. Gait dysfunction in corticobasal degeneration is variable, and depends upon the limb(s) involved and the specific symptoms present, for instance dystonia or parkinsonism.
GAIT INTERVENTIONS A multidomain intervention strategy is required to treat gait disorders. The focus of treatment in individuals with gait and cognitive disorders is to identify and treat underlying causes including dementia, address mobility limitations through rehabilitation and other approaches, and prevent complications such as falls.
Rehabilitation and exercise Physical therapy can help strengthen weak muscles, improve balance, and teach compensatory gait strategies. An aerobic exercise regimen and a program aiming to improve fitness and tone both improved Timed Up and Go performance and time needed to climb stairs (Gothe et al., 2014). Complex motor tasks that have substantial cognitive components, such as dance, can improve physical function (e.g., Kattenstroth et al., 2013). Various types of dance have also been studied
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in PD, where it has been found to improve various aspects of gait dysfunction (Hackney and Earhart, 2009, 2010; Hackney et al., 2015). Both physiotherapy (Tomlinson et al., 2013) and aerobic exercise (Shu et al., 2014) have also been shown to improve gait in PD.
Cognitive training Exercise programs and physical therapy are beneficial, yet difficult for most people to maintain for prolonged time periods. They may also not be possible in those with significant pain, mobility limitations, or other significant medical comorbidities, who might benefit the most from improved walking. Therefore, training programs targeting the cognitive domains that subserve gait have been studied for their ability to improve walking in older adults. Cognitive training exercises, generally computer-based and without any motor component, can improve gait (Verghese et al., 2010; Smith-Ray et al., 2014) and balance (Li et al., 2010; SmithRay et al., 2014).
Medications Low vitamin D levels are associated with slower walking speed and worse strength (Wicherts et al., 2007; Mastaglia et al., 2011), worse balance (Wicherts et al., 2007), increased gait variability (Beauchet et al., 2011b), and increased decline in gait over time (Wicherts et al., 2007). Vitamin D supplementation may improve gait (Muir and Montero-Odasso, 2011), though it is unclear if supplementation reduces fall risk over time (BischoffFerrari et al., 2004; Michael et al., 2010; Murad et al., 2011; Gillespie et al., 2012). This benefit may be stronger in those with baseline vitamin D deficiency and those who receive vitamin D with calcium (Murad et al., 2011). Treatment of the underlying neurodegenerative disease may be effective in improving gait. In those with mild AD, cholinesterase inhibitors may improve gait velocity (Montero-Odasso et al., 2015), though the effects on improvement in gait variability are mixed (Beauchet et al., 2014b; Montero-Odasso et al., 2015). Both dopaminergic medications and deep brain stimulation can improve some aspects of gait in those with PD (McNeely and Earhart, 2013). In those with Huntington’s disease, treating chorea with tetrabenazine results in improvements in gait and balance (Kegelmeyer et al., 2014). In those with multiple sclerosis, dalfampridine may be used specifically to improve gait (Egeberg et al., 2012). Certain classes of medications may worsen gait, though more research is needed to clarify the underlying mechanisms (e.g., Donoghue et al., 2015; George and Verghese, 2016). Numerous medications, in particular sedatives and hypnotics, increase the risk of falls in older
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adults (Huang et al., 2012), though further discussion is beyond the scope of this chapter.
CONCLUSION There are strong relationships between gait and cognition. They can each be used to elucidate the underlying physiology of the other. Changes in gait can be used as clinical markers of nervous system pathology, allowing for earlier identification of neurodegenerative disease. Gait dysfunction is common in neurodegenerative disease and dementia, and a crucial part of managing people with dementia is assessment of gait. Treatment of dementia can improve gait. Learning more about these relationships will hopefully allow continued improvement in patient care.
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