Aging, the Central Nervous System, and Mobility in Older Adults: Neural Mechanisms of Mobility Impairment

Abstract

Background.

Mobility is crucial for successful aging and is impaired in many older adults. We know very little about the subtle, subclinical age-related changes in the central nervous system (CNS) that mediate mobility impairment.

Methods.

A conference series focused on aging, the CNS, and mobility was launched. The second conference addressed major age-associated mechanisms of CNS-mediated mobility impairment. Speakers and conference attendees recommended key areas for future research, identified barriers to progress, and proposed strategies to overcome them.

Results.

Priorities identified for future research include (a) studying interactions among different mechanisms; (b) examining effects of interventions targeting these mechanisms; (c) evaluating the effect of genetic polymorphisms on risks and course of age-related mobility impairment; and (d) examining the effect of age on CNS repair processes, neuroplasticity, and neuronal compensatory mechanisms. Key strategies to promote research include (a) establish standard measures of mobility across species; (b) evaluate the effect of aging in the absence of disease on CNS and mobility; and (c) use advanced computational methods to better evaluate the interactions between CNS and other systems involved in mobility.

Conclusions.

CNS is a major player in the process, leading to mobility decline with aging. Future research in this area has the potential to prolong independence in older persons. Better interactions among disciplines and shared research paradigms are needed to make progress. Research priorities include the development of innovative approaches to integrate research on aging, cognition, and movement with attention to neurovascular function, neuroplasticity, and neurophysiological reserve.

Disorders of gait and mobility are major causes of morbidity and mortality in older adults (1). Age-related mobility disorders are multifactorial; potential contributors include a myriad of diseases, drugs, and environmental hazards very often in combination. A central theme in age-related mobility research is to understand the relevant mechanisms and synergistic interactions between contributing system impairments and compensatory mechanisms that may explain the variations in mobility impairment observed among older adults. The central nervous system (CNS), through various cognitive, sensory, autonomic, and motor networks, plays a key role in the control of mobility, but much of the work related to the CNS has focused on specific conditions rather than aging (2). To promote further research on the role of the CNS in mobility limitations of aging, and to foster collaboration among experts within and beyond the field of aging who study the CNS and mobility, three workshops were coordinated by the Gerontological Society of America, the National Institute on Aging, and the University of Pittsburgh. The overarching goal of these workshops was to promote crossdisciplinary research in age-related, CNS-mediated mobility decline and to facilitate the translation of this research into interventions that enhance mobility in the aging population.

The first workshop, completed in 2012, consolidated the existing evidence supporting a relationship between the CNS and mobility in the context of other contributors and identified additional goals for future work (2). In 2013, the second workshop, described in this article, explored neuronal mechanisms underpinning mobility impairments in older adults. Workshop 3, completed in November 2014, focused on novel interventions to prevent or treat mobility limitations.

The goals of the 2013 workshop were (a) to explore age-related neural mechanisms of mobility disability that may serve as targets for future preventive and therapeutic interventions; (b) to review previous research, on ischemia; inflammation; abnormal protein deposition; metabolic, hormonal, and neurotrophic processes; genetic factors; and other pathological processes that disrupt neural networks responsible for gait and balance; (c) to identify the compensatory role of the CNS in maintaining mobility despite pathology in other systems; and (d) to identify gaps in knowledge and stimulate future crossdisciplinary research. In this article, key findings for these topics are presented, followed by conference recommendations regarding gaps in knowledge and future research directions.

Methods

The workshop was held prior to the 2013 Annual Meeting of the Gerontological Society of America in New Orleans on November 19–20. Based on recommendations from the Planning Committee, it was organized into four subtopics (a) Neurovascular Mechanisms; (b) Inflammation; (c) Genetic and Metabolic Mechanisms; and (d) Neuromotor Control and Networks. Attendees represented gerontology, epidemiology, neurology, rehabilitation, neuroimaging, basic science, animal models, and clinical research. Scientific sessions were followed by roundtable discussions to make recommendations about (a) key areas for future research and (b) barriers to research in these key areas; and (c) strategies to overcome these barriers. The tables/groups arrived at a consensus through group discussions. Some recommendations were unique to a specific topic, whereas others were more general. The unique recommendations are presented by topic, whereas the general ones are summarized in tables.

Although the content from this workshop can only be briefly summarized here, additional information is available in Supplementary Material.

Results

Neurovascular Mechanisms

There is a strong link between vascular risk factors, pathological changes, and impaired mobility (for detailed review, see references 30–34 in the Supplementary Material). Among the vascular risk factors, hypertension has been significantly linked to impaired mobility. Hypertension is associated with worse gait function (3), and higher blood pressures accelerate slowing of gait speed in well-functioning older adults over 18 years of follow-up (4). In addition to hypertension, systemic vascular disease, such as arterial stiffness (5), has also been associated with slower gait at baseline and a greater future decline in gait speed. Radiographic cerebral small vessel disease has also been associated with impaired mobility, including falls and impaired balance, gait, and stepping (6–9).

In addition to structural brain changes, functional cerebrovascular changes measured by transcranial Doppler (TCD) ultrasound have also been linked to MRI markers of cerebral small vessel disease as well as mobility impairment in older age. Impaired cerebral vasoreactivity (blood flow responses to end-tidal CO₂; a measure of endothelial function in the brain) (10) and pulsatility index (a measure of vascular stiffness in the brain) (11) have both been associated with white matter hyperintensities (WMH), whereas impaired cerebral autoregulation (blood flow responses to blood pressure) has been linked to disrupted brain white matter microstructural integrity using diffusion tensor imaging (12). Impaired cerebral vasoreactivity has also been associated with slow gait and falls in older age (13). Neurovascular coupling (cerebral blood flow responses to motor or cognitive activation), which is also impaired in slow walkers, may represent a physiological measure of reserve which can compensate for the presence of WMH (14).

Knowledge Gap: Neurovascular Mechanisms

Cerebral small vessel disease, which is strongly linked to mobility impairment, is the most common pathology in the human aging brain. It is also a complex and heterogeneous disorder involving both arteriolar and venous pathology. Most studies have focused on the arteriolar pathologies, such as increased tortuosity and lipohyalinosis. However, the contribution of venous pathologies to radiographic manifestations of small vessel disease should also be considered, including venous collagenosis in the intramedullary veins and venous stenosis in the deep periventricular venules (15,16). Furthermore, cerebral small vessel disease has multiple manifestations including lacunar strokes, WMH, cerebral microbleeds, enlarged perivascular spaces, and microinfarcts. Thus, to harmonize our research methodologies and radiographic outcomes, we need to standardize image-based reporting of cerebral small vessel disease. For a detailed review of the recommended neuroimaging standards for small vessel disease, please see references (17) and (18).

In addition, much of our current knowledge of neurovascular mechanisms in the brain is based on association studies and our understanding of the sequence of events and causal pathways leading to structural brain damage is limited. We do not have an understanding of early cerebrovascular changes before they result in permanent brain injury. The contribution of genetic and epigenetic factors, inflammation and oxidative stress to these age-related neurovascular changes in humans remain largely unexplored. Similarly, the mechanisms underpinning compensation and variable expression of mobility impairment are also unknown.

Future Research: Neurovascular Mechanisms

We need to standardize terminology and definitions for microvascular disease, including imaging and neuropathological criteria along with cognitive and mobility-related manifestations. We should further examine the pathologies underlying findings from advanced imaging techniques such as arterial spin labeling, diffusion tensor imaging, magnetization transfer ratio imaging, and resting state functional MRI, and relate them to abnormalities in gait, balance, and cognitive function. Future studies should examine mechanisms and pathways linking vascular function to mobility, not only in the presence of disease but also in apparently normal biological aging. Most importantly, we need to move away from studying, almost exclusively, end-stage brain ischemic pathology where mobility impairment may be irreversible. Future research should focus instead on deciphering preclinical changes predictive of mobility impairment, which may be more amenable to intervention. For example, the potential for endothelial repair by endothelial stem cells released by the bone marrow holds great promise for improving vascular function. The release of these stem cells, which can be stimulated by exercise as well and by injection of growth factors (granulocyte-macrophage colony-stimulating factor), has already been shown to repair endothelial function in the peripheral arteries (19).

Genetic and Metabolic Mechanisms

Metabolic and hormonal pathways, as well as genetic polymorphisms, play a key role in the expression of brain injury, in the recovery from injury, and in neuroplasticity. The strong link between hypertension, vascular dysfunction, and brain injury has prompted the examination of metabolic and hormonal pathways that could link these conditions. One such pathway is the renin–angiotensin system that regulates blood pressure and fluid balance by acting on various target organs including the vasculature. There is also evidence for an independent brain renin–angiotensin system involved in most brain functions (20), but studies linking this pathway to mobility measures are currently lacking.

Genetic disorders that manifest as cerebral small vessel disease provide a unique opportunity to study vascular mechanisms of cerebral injury and clinical manifestations of gait and mobility impairment. One example is cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which results from a mutation of the Notch 3 gene on Chromosome 19 (21). Patients with CADASIL develop subcortical strokes and accumulate MRI markers of small vessel disease including WMH, lacunar infarctions, cerebral microbleeds, and brain atrophy (22). Clinically, they experience migraine headaches, mood disorders (depression and apathy) (23), mobility impairment (24), and cognitive dysfunction (25). Interestingly, the degree of brain atrophy is the most important factor in disease-associated cognitive impairment and disability in patients with CADASIL (22).

Finally, as the mechanistic pathways leading to CNS dysfunction and mobility impairment are elucidated, the vast potential for neuroplasticity within the brain becomes striking (26). For example, brain-derived neurotrophic factor (BDNF) plays a critical role in neuroprotection, angiogenesis, and synaptic plasticity (27). “Designer” BDNF drugs may improve functional recovery (28). Polymorphisms in the human BDNF gene have been shown to impact the individual’s capacity for plasticity. The BDNF met allele is associated with impaired motor skill learning and has been shown to impair recovery from stroke (29). Similar associations have been reported with APOE polymorphisms (30). Indeed, there is a constellation of genetic markers involving both extracellular (BDNF, nerve growth factor, Dopamine, Serotonin) and intracellular (PDEI, ACE, CREB, CamKII, MAPK, ERK) signaling proteins that have been linked to rehabilitation potential and are considered plasticity genes (31). The concept of “therapogenomics,” based on the constellation of plasticity genes, may be one promising approach to help us identify optimal neural strategies to enhance neurorecovery.

Knowledge Gap: Genetic and Metabolic Mechanisms

Although metabolic and hormonal pathways and genetic polymorphisms have been linked to brain injury and neuroplasticity, there are no direct links to measures of mobility. Our understanding of the cascade of events that proceed from hypertension to mobility limitation is incomplete. Similarly, our knowledge of mobility in individuals with CADASIL is very limited. The high variability of disease severity and mobility limitation, even within families with the same Notch3 mutation, may signal as yet unknown compensatory mechanisms.

The link between neuronal plasticity and rehabilitation is emerging, but mechanisms underlying this link are not known. For this reason, research in clinical neurorehabilitation has lagged behind basic research on neuronal plasticity, so that the critical interplay between neuroplasticity, clinical recovery, and rehabilitation is just beginning to emerge (26). Better interactions among basic and clinical scientists in these fields are essential for developing better motor rehabilitation interventions for older adults. The most important driver of plasticity is practice and experience. Neural signals can be exploited clinically using neurophysiological (rTMS, TDCS) or neuropharmacological (l-DOPA or Fluoxetine) interventions to improve relearning and rehabilitation (26,32). There is great potential to more fully elucidate the role of pharmacogenomics and/or pharmacotherapy in neurorehabilitation.

Future Research: Genetic and Metabolic Mechanisms

Interventions targeting the renin–angiotensin system system can help clarify the mechanisms linking renin–angiotensin system to CNS outcomes and identify therapeutic targets for preventing mobility impairment. The relationship between disease pathology in CADASIL and gait function can provide insights into neural mechanisms of altered mobility. We should develop and implement reproducible motor rehabilitation protocols and identify viable pharmacologic compounds that selectively drive specific neural signaling pathways and promote neural plasticity and recovery in combination with therapeutic exercise. The role of genetics in human neural plasticity and neurorehabilitation requires further study and can result in genomics informing motor rehabilitation programs.

Inflammation and Bioenergetics

Neurodegeneration and inflammation alter brain function and result in disorders of mobility. Neurodegenerative disorders such as Parkinson’s disease (PD) provide an opportunity to examine CNS molecular pathways linked to mobility impairment which may also be relevant in biological aging. PD was generally recognized as a movement disorder attributed to the death of dopamine-generating cells. Emerging evidence implicates defects in the mitochondrial electron transport chain and biogenesis which are regulated by the peroxisome proliferator-activated receptor γ coactivator-1α (PCG-1α). PCG-1α plays a central role in regulating mitochondrial function as well as inflammation in PD and its associated mobility impairment (33).

Multiple sclerosis (MS), which is a CNS neuroinflammatory disorder, results in demyelination of the brain and spinal cord and leads to disorders of mobility and cognition. There are two components to MS: an inflammatory (relapsing remitting MS) and a neurodegenerative (chronic progressive MS) component. The inflammatory component shares a genetic architecture with autoimmune diseases. The neurodegenerative component is not well understood. Chronic progressive MS has a slightly later onset than relapsing remitting MS, and brain atrophy accelerates starting with the first relapse. The neurodegenerative component is proposed to be a disorder of innate immunity (ie, with microglia, astrocytes, monocytes, and dendritic cell involvement) as opposed to the inflammatory component (ie, relapsing remitting MS), which is a disorder of adaptive immunity (ie, involvement of antigen-specific T cells, and B cells). Therefore, considering MS as a CNS inflammatory and neurodegenerative disorder may provide a model linking CNS inflammation and neurodegeneration to mobility impairment with similarities to PD and Alzheimer’s disease (34).

Systemic aging has also been associated with a proinflammatory state characterized by persistent low grade IL-6 and C-reactive protein (CRP) activation. This profile is differentiated from an acute inflammatory reaction where there is an acute burst of high serum levels of IL-6 and CRP, which then rapidly normalize during the healing/resolution phase. For example, frailty is an age-related syndrome that has been shown to be associated with a chronic inflammatory profile with elevated IL-6, CRP, WBC, and neopterin levels and low Hgb and IGF-1 levels (35). Clinically, frailty often involves alterations in mobility. Age-related chronic inflammation and its relation to mobility in the absence of frailty are not well studied.

Knowledge Gap: Inflammation and Bioenergetics

The mechanisms responsible for individual variability in mobility decline in PD, MS, and aging remain poorly understood. Although the presence of neurodegeneration in PD and CNS inflammation in MS have been linked to mobility impairment, the potential roles of cerebral PGC-1 activity, activation of innate immunity, and low grade inflammation in age-related mobility impairments are not known.

Future Research: Inflammation and Bioenergetics

The potential link between chronic systemic inflammation and age-related mobility decline should be examined. There is a clear need to apply what we have learned in PD and MS to studies of mobility decline in aging and to determine whether the hypotheses generated from our knowledge in MS and PD are applicable to age-related mobility decline. We should perform “omics’ studies in aging similar to those that are now being conducted in neurodegenerative and neuroinflammatory disorders. This would allow us to systematically delineate all molecules and all pathways—genetic variants, all transcripts, all metabolites—linked to mobility impairment in human aging using genome-wide approaches in human brain collections (and possibly in animal models) that span humans of all ages and pathological and clinical phenotypes. This approach would create a rich genomic and phenotypic database-linked biobank that could lead to the identification of new mechanisms or help us better understand some of the mechanisms discussed in this workshop.

Neuromotor Control and Other Network Studies

There is a diverse literature on the physiological and functional manifestations of age-related alterations in neuromuscular function, neural activation in the brain, and neural coordination of movement. The specific etiology of age-related impaired neuromuscular activation remains unclear but likely includes CNS mechanisms (those described in earlier sections) as well as altered structure and function of motor units. Decline in voluntary neuromuscular activation contributes to weakness prior to the onset of changes in walking speed (36), and older adults who exhibit mild mobility deficits have lower voluntary neuromuscular activation than high functioning older adults (37). Recent work has shown that neuromuscular activation impairment may be partially restored by power resistance training, which also partially restores mobility function (38). Future research is needed to investigate the specific mechanisms underlying the decline of neuromuscular activation, as well as the potential therapies (behavioral, pharmacological, genetic, etc) that may optimally prevent or reverse this defect.

Despite the seemingly automatic nature of mobility tasks such as balance and walking, it is now clear that cortical processing is required for continuous predictive and reactive control. The most well-known evidence comes from “dual-task” paradigms (39), in which performance is compromised for one or both tasks compared with performance during single-task conditions. The need for cortical control of mobility is likely due to the complexity of bipedal locomotion including navigation (40), transition, (41) and sensorimotor control (42). It is also important to acknowledge the potential contributions of other systems to mobility function. For example, it has been shown that phasic autonomic reactions are temporally coupled to balance reactions (43), whereas sensory perception in certain plantar regions is associated with mobility function (44).

Given the complexity of mobility as a behavior, important insights to the CNS control of mobility (as well as age-related changes in this control) can be gained from systems level investigations. Particularly in the context of neuroimaging, systems level investigations are increasingly popular approaches that have the potential to reveal the neural networks that facilitate dynamic interactions among various brain regions. The nature of these interactions is likely crucial to the resultant emergent behaviors, such as gait, vision, or cognition. Once the topology of these network connections is established, an evaluation of the flow through these networks can help to explain age-related differences in behaviors. This approach has recently been used to evaluate differences in the neural networks for mobility in older adults with high, moderate, and low scores on the short physical performance battery (45). Those with low scores can be differentiated from those with moderate or high scores based on the consistency of the motor network. Furthermore, those with high scores could be differentiated from those with moderate and low scores based on the number of second-degree motor connections within the network. It is likely that the complexity of these network connections with respect to their number of connections and the strength of interactions may form the substrate for brain reserve and plasticity, which are crucial for preserving mobility by buffering the system against age-related impairments.

Knowledge Gap: Neuromotor Control and Other Network Studies

The specific mechanisms driving age-related changes in neuronal control remain unclear. Contribution of vascular disease or neuroinflammation to altered brain network organization, impaired voluntary neuromuscular activation, and compromised reactive balance is not known. Understanding these relationships will be crucial for optimizing therapeutic interventions to prevent and/or reverse mobility impairment. There is also a need to better understand the functions of brain regions and networks in the control of mobility. Development of quantitative tools to assess the temporal and spatial dynamics between neuromotor control processes and mobility behaviors is necessary. The use of averaging and standard statistical analysis is insufficient for capturing the holistic nature of complex behaviors such as mobility.

Future research: neuromotor control and other network studies

To move this field forward, multidisciplinary approaches are needed. New computational approaches (eg, computer models, mathematics, etc.) will facilitate a systems approach to quantifying complex mobility behaviors. We should rely less on reductionist study designs and interpretations but rather embrace a “holistic-view” of mobility that encompasses many different neural control functions interacting across different scales in time and space. Qualitative methods that take into account biological heterogeneity are also needed. Finally, there is a need for studies to generate data linking basic mechanistic research (eg, central, peripheral, and autonomic nervous system integrity), applied mechanistic research (eg, EMG, functional MRI), and functional outcomes.

Recommendations

The recommendations from the conference attendees are summarized in Tables 1 and 2. In addition to mobility, gait and balance are essential cognitive motor functions. Akin to global cognition, for which we can describe different profiles of impairment (ie, cognitive domains), we need to identify profiles and domains of mobility impairment relevant to different disease states and underlying mechanisms across these disease states. We need to develop a consensus on harmonized measures of mobility that are quantitative and can integrate the various aspects of mobility across different domains to ensure that we collect data in a way that allows comparison across centers and populations. Future studies should incorporate mobility as an outcome and develop novel tools that help probe mechanisms and causal pathways linking CNS to age-related mobility decline and to its variable clinical expression. These studies will help us understand mobility in the context of brain networks, cognition, neuromuscular activation, and the autonomic nervous system. Clearly, there are feasible next steps that build on new and existing methods but integrate multidisciplinary perspectives, collaborations between clinical and basic scientists, and an aging perspective on mobility as a key to independence in late life.

Table 1.

Roundtable Discussion: Future Research

Key Areas for Future Research
Longitudinal studies of mechanistic connections between neuropathological changes, inflammation, ischemia, genetic polymorphisms, gene expression, and other biological processes in the brain and the development of mobility impairments in animals and humans across the life span
Studies that manipulate components of genetic, molecular, structural, and/or social networks to determine their effects on specific measures of mobility in animals and humans
Studies that employ unique gerontologic approaches to explore the effects of biological aging on the CNS and mobility (parabiosis, caloric restriction, administration of longevity molecules) in the absence of disease
Study the impact of genetic polymorphisms on the CNS control of mobility (eg, BDNF Met allele impairs plasticity, motor driving, and stroke recovery)
Study age-related changes in tissue maintenance, repair, and plasticity in the CNS and their effects on mobility
Identify compensatory mechanisms that explain intra-individual variability and enable some people, but not others, to adapt to various pathologies

Note: BDNF = brain-derived neurotrophic factor; CNS = central nervous system.

Table 2.

Roundtable Discussion: Barriers to Future Research and Strategies to Overcome Barriers

Barrier	Strategy
Variable definition of mobility impairment	Define mobility and harmonize our measures.
	What should studies measure as an outcome?
Absence of multidisciplinary studies	Develop uniform, standardized measures and nomenclature to facilitate crossinstitutional animal and human studies
	Harmonize our imaging protocols and techniques
	Build data repositories of common blood, tissue, and mobility measures that are made publicly available
	Develop crossdisciplinary educational programs and collaborations in order to implement our newly developed tools from bioinformatics, bioengineering, “omics,” neuroimaging, and neurophysiology that are capable of studying a complex behavior such as mobility in the context of molecular, cellular, biological, and physiological machinery that work in unison to achieve it
How does CNS control mobility in biological aging	Use healthy older animals that facilitate the study of interactions between aging and CNS mechanisms responsible for mobility in the absence of disease
How is the control of mobility integrated across CNS, PNS, and ANS	Develop dynamic measures and analytic techniques that are capable of quantifying temporal and spatial changes in biologic and physiologic processes from CNS gene expression to functional MRI measures
	Develop more proximal, quantifiable measures of CNS outputs that control mobility, such as nerve traffic at neuromuscular junctions during mechanistic experiments, dendritic sprouting during various stimuli, and molecular imaging of neurotransmitters or inflammatory mediators during aging

Notes: ANS = autonomic nervous system; CNS = central nervous system; PNS = peripheral nervous system.

Supplementary Material

Supplementary material can be found at: http://biomedgerontology.oxfordjournals.org/

Funding

This work was supported by a cooperative conference grant (National Institute on Aging, U13-AG-041613-01), the University of Pittsburgh Claude D. Pepper Older Americans Independence Center (National Institute on Aging, P30-AG-024827), a postdoctoral training grant (National Institute on Aging, T32-AG-000181), and RO1-NS-085002.