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1.  Extra-nigral pathologies are common in Parkinson disease with freezing of gait: an in vivo PET study 
Cholinergic denervation has been associated with falls and slower gait speed and β-amyloid deposition with greater severity of axial motor impairments in Parkinson disease (PD). However, little is known about the association between the presence of extra-nigral pathologies and freezing of gait (FoG).
Patients with PD (n=143; age 65.5±7.4 years, Hoehn and Yahr stage 2.4±0.6, Montreal Cognitive Assessment score 25.9±2.6) underwent [11C]methyl-4-pi-peridinyl propionate acetylcholinesterase and [11C]dihydrotetrabenazine dopaminergic PET imaging, and clinical, including FoG, assessment in the dopaminergic “off” state. A subset of subjects (n=61) underwent [11C]Pittsburgh compound-B β-amyloid PET imaging. Normative data were used to dichotomize abnormal β-amyloid uptake or cholinergic deficits.
FoG was present in 20 patients (14.0%). Freezers had longer duration of disease (P=0.009), more severe motor disease (P<0.0001) and lower striatal dopaminergic activity (P=0.013) compared to non-freezers. FoG was more common in patients with diminished neocortical cholinergic innervation (23.9%, χ2=5.56, P=0.018) but not in the thalamic cholinergic denervation group (17.4%, χ2=0.26, P=0.61). Subgroup analysis showed higher frequency of FoG with increased neocortical β-amyloid deposition (30.4%, Fisher Exact test: P = 0.032). FoG frequency was lowest with absence of both pathology (4.8%), intermediate in subjects with single extra-nigral pathology (14.3%) and highest with combined neocortical cholinopathy and amyloidopathy (41.7%; Cochran-Armitage trend test Z=2.63, P=0.015). Within the group of freezers, 90% had at least one of the two extra-nigral pathologies studied.
Extra-nigral pathologies, in particular the combined presence of cortical cholinopathy and amyloidopathy, are common in PD with FoG and may contribute to its pathophysiology.
PMCID: PMC4162130  PMID: 24909584
acetylcholine; β-amyloid; dopamine; gait freezing; Parkinson’s disease; PET
2.  Callosal Hyperintensities and Gait Speed Gain from Two Types of Mobility Interventions in Older Adults 
Corpus callosum, the largest white matter tract in the brain, is prone to small-vessel disease in older adults. White matter hyperintensities (WMH) are neuroimaging markers of small-vessel disease. WMH in the genu and splenium of the corpus callosum are associated with slow gait in older adults. We assessed whether the volume of callosal hyperintensities in the genu and splenium of older adults with mobility impairment are differentially associated with degree of gain in gait speed following two types of gait interventions.
Single-blind randomized control trial of two types of gait exercises in older adults.
Research center in an academic institution.
Ambulatory adults aged 65 and older with a slow and variable gait.
12-week physical therapist guided trial of a conventional walking, endurance, balance and strength (WEBS) intervention (n=20) vs a timing and coordination of gait (TC) intervention (n=22).
Main outcome measure
Gain in gait speed following intervention and its relationship to callosal hyperintensities in the genu and splenium of corpus callosum.
Gait speed improved in the WEBS (mean change, 0.16m/s) and TC groups (mean change, 0.21m/s), both p<0.05. WMH volume in the genu was differentially associated with gait speed gain (Group x genual WMH interaction, p=0.05). Greater genual WMH volume was related to a smaller gait speed gain in the WEBS (p=0.01) but not in the TC (p=0.1) group. Splenial WMH volume was not differentially associated with gait speed gain (interaction, p=0.9).
Callosal hyperintensities differentially influence gait speed gain by type of gait rehabilitation. Mobility impaired older adults with genual hyperintensities may benefit from a rehabilitation program focused on motor-skill learning rather than on strength and endurance training.
PMCID: PMC4394027  PMID: 25316182
corpus callosum; white matter hyperintensities; cognition; mobility; gait rehabilitation
3.  Higher Step Length Variability Indicates Lower Grey Matter Integrity of Selected Regions in Older Adults 
Gait & posture  2014;40(1):225-230.
Step length variability (SLV) increases with age in those without overt neurologic disease, is higher in neurologic patients, is associated with falls, and predicts dementia. Whether higher SLV in older adults without neurologic disease indicates presence of neurologic abnormalities is unknown. Our objective was to identify whether SLV in older adults without overt disease is associated with findings from multimodal neuroimaging. A well-characterized cohort of 265 adults (79–90 years) was concurrently assessed by gait mat, magnetic resonance imaging with diffusion tensor, and neurological exam. Linear regression models adjusted for gait speed, demographic, health, and functional covariates assessed associations of MRI measures (grey matter volume, white matter hyperintensity volume, mean diffusivity, fractional anisotropy) with SLV. Regional distribution of associations was assessed by sparse partial least squares analyses. Higher SLV (mean: 8.4, SD: 3.3) was significantly associated with older age, slower gait speed, and poorer executive function and also with lower grey matter integrity measured by mean diffusivity (standardized beta=0.16; p=0.02). Associations between SLV and grey matter integrity were strongest for the hippocampus and anterior cingulate gyrus (both β=0.18) as compared to other regions. Associations of SLV with other neuroimaging markers were not significant. Lower integrity of normal-appearing grey matter may underlie higher SLV in older adults. Our results highlighted the hippocampus and anterior cingulate gyrus, regions involved in memory and executive function. These findings support previous research indicating a role for cognitive function in motor control. Higher SLV may indicate focal neuropathology in those without diagnosed neurologic disease.
PMCID: PMC4071448  PMID: 24792638
gait disorders; diffusion tensor imaging; aging; brain
4.  Prediction of responders for outcome measures of Locomotor Experience Applied Post Stroke trial 
The Locomotor Experience Applied Post Stroke rehabilitation trial found equivalent walking outcomes for body weight-supported treadmill plus overground walking practice versus home-based exercise that did not emphasize walking. From this large database, we examined several clinically important questions that provide insights into recovery of walking that may affect future trial designs. Using logistic regression analyses, we examined predictors of response based on a variety of walking speed-related outcomes and measures that captured disability, physical impairment, and quality of life. The most robust predictor was being closer at baseline to the primary outcome measure, which was the functional walking speed thresholds of 0.4 m/s (household walking) and 0.8 m/s (community walking). Regardless of baseline walking speed, a younger age and higher Berg Balance Scale score were relative predictors of responding, whether operationally defined by transitioning beyond each speed boundary or by a continuous change or a greater than median increase in walking speed. Of note, the cutoff values of 0.4 and 0.8 m/s had no particular significance compared with other walking speed changes despite their general use as descriptors of functional levels of walking. No evidence was found for any difference in predictors based on treatment group.
Clinical Trial Registration; NCT00243919, “Locomotor Experience Applied Post Stroke Trial”;
PMCID: PMC4374620  PMID: 24805892
community ambulation; exercise; functional walking level; gait speed; LEAPS; outcome measures; physical therapy; quality of life; stroke rehabilitation; walking
5.  Aging, the Central Nervous System, and Mobility 
Mobility limitations are common and hazardous in community-dwelling older adults but are largely understudied, particularly regarding the role of the central nervous system (CNS). This has limited development of clearly defined pathophysiology, clinical terminology, and effective treatments. Understanding how changes in the CNS contribute to mobility limitations has the potential to inform future intervention studies.
A conference series was launched at the 2012 conference of the Gerontological Society of America in collaboration with the National Institute on Aging and the University of Pittsburgh. The overarching goal of the conference series is to facilitate the translation of research results into interventions that improve mobility for older adults.
Evidence from basic, clinical, and epidemiological studies supports the CNS as an important contributor to mobility limitations in older adults without overt neurologic disease. Three main goals for future work that emerged were as follows: (a) develop models of mobility limitations in older adults that differentiate aging from disease-related processes and that fully integrate CNS with musculoskeletal contributors; (b) quantify the contribution of the CNS to mobility loss in older adults in the absence of overt neurologic diseases; (c) promote cross-disciplinary collaboration to generate new ideas and address current methodological issues and barriers, including real-world mobility measures and life-course approaches.
In addition to greater cross-disciplinary research, there is a need for new approaches to training clinicians and investigators, which integrate concepts and methodologies from individual disciplines, focus on emerging methodologies, and prepare investigators to assess complex, multisystem associations.
PMCID: PMC3805295  PMID: 23843270
Motor control; Central nervous system; Mobility.
6.  Motor Learning Versus StandardWalking Exercise in Older Adults with Subclinical Gait Dysfunction: A Randomized Clinical Trial 
Journal of the American Geriatrics Society  2013;61(11):10.1111/jgs.12506.
Current exercise recommendationsfocus on endurance and strength, but rarely incorporate principles of motor learning. Motor learning exerciseis designed to address neurological aspects of movement. Motor learning exercise has not been evaluated in older adults with subclinical gait dysfunction.
Tocompare motor learning versus standard exercise on measures of mobility and perceived function and disability.
Single-blind randomized trial.
University research center.
Olderadults (n=40), mean age 77.1±6.0 years), who had normal walking speed (≥1.0 m/s) and impaired motor skill (Figure of 8 walk time > 8 s).
The motor learning program (ML) incorporated goal-oriented stepping and walking to promote timing and coordination within the phases of the gait cycle. The standard program (S) employed endurance training by treadmill walking.Both included strength training and were offered twice weekly for one hour for 12 weeks.
Primary outcomes included mobility performance (gait efficiency, motor skill in walking, gait speed, and walking endurance)and secondary outcomes included perceived function and disability (Late Life Function and Disability Instrument).
38 of 40 participants completed the trial (ML, n=18; S, n=20). ML improved more than Sin gait speed (0.13 vs. 0.05 m/s, p=0.008) and motor skill (−2.2 vs. −0.89 s, p<0.0001). Both groups improved in walking endurance (28.3 and 22.9m, but did not differ significantly p=0.14). Changes in gait efficiency and perceived function and disability were not different between the groups (p>0.10).
In older adults with subclinical gait dysfunction, motor learning exercise improved some parameters of mobility performance more than standard exercise.
PMCID: PMC3827693  PMID: 24219189
exercise; motor learning; clinical trial
7.  Gait speed in Parkinson disease correlates with cholinergic degeneration 
Neurology  2013;81(18):1611-1616.
We investigated dopaminergic and cholinergic correlates of gait speed in Parkinson disease (PD) and non-PD control subjects to test the hypothesis that gait dysfunction in PD may result from multisystem degeneration.
This was a cross-sectional study. Subjects with PD but without dementia (n = 125, age 65.6 ± 7.3 years) and elderly subjects without PD (n = 32, age 66.0 ± 10.6 years) underwent [11C]dihydrotetrabenazine dopaminergic and [11C]methyl-4-piperidinyl propionate acetylcholinesterase PET imaging, and cognitive and clinical testing, including an 8.5-m walk in the dopaminergic “off” state. The fifth percentile of cortical cholinergic activity in the elderly without PD was used to define normal-range activity in the subjects with PD.
Normal-range cortical cholinergic activity was present in 87 subjects with PD (69.6%). Analysis of covariance using gait speed as the dependent variable demonstrated a significant model (F = 6.70, p < 0.0001) with a significant group effect (F = 3.36, p = 0.037) and significant slower gait speed in the low cholinergic PD subgroup (0.97 ± 0.22 m/s) with no significant difference between the normal-range cholinergic PD subgroup (1.12 ± 0.20 m/s) and control subjects (1.17 ± 0.18 m/s). Covariate effects were significant for cognition (F = 6.58, p = 0.011), but not for striatal dopaminergic innervation, sex, or age.
Comorbid cortical cholinergic denervation is a more robust marker of slowing of gait in PD than nigrostriatal denervation alone. Gait speed is not significantly slower than normal in subjects with PD with relatively isolated nigrostriatal denervation.
PMCID: PMC3806920  PMID: 24078735
8.  Walking Smoothness Is Associated With Self-Reported Function After Accounting for Gait Speed 
Gait speed has shown to be an indicator of functional status in older adults; however, there may be aspects of physical function not represented by speed but by the quality of movement. The purpose of this study was to determine the relations between walking smoothness, an indicator of the quality of movement based on trunk accelerations, and physical function.
Thirty older adults (mean age, 77.7±5.1 years) participated. Usual gait speed was measured using an instrumented walkway. Walking smoothness was quantified by harmonic ratios derived from anteroposterior, vertical, and mediolateral trunk accelerations recorded during overground walking. Self-reported physical function was recorded using the function subscales of the Late-Life Function and Disability Instrument.
Anteroposterior smoothness was positively associated with all function components of the Late-Life Function and Disability Instrument, whereas mediolateral smoothness exhibited negative associations. Adjusting for gait speed, anteroposterior smoothness remained associated with the overall and lower extremity function subscales, whereas mediolateral smoothness remained associated with only the advanced lower extremity subscale.
These findings indicate that walking smoothness, particularly the smoothness of forward progression, represents aspects of the motor control of walking important for physical function not represented by gait speed alone.
PMCID: PMC3779630  PMID: 23689828
Gait; Motor control; Physical function.
9.  Prevalence of and interventions for sarcopenia in ageing adults: a systematic review. Report of the International Sarcopenia Initiative (EWGSOP and IWGS) 
Age and Ageing  2014;43(6):748-759.
Objective: to examine the clinical evidence reporting the prevalence of sarcopenia and the effect of nutrition and exercise interventions from studies using the consensus definition of sarcopenia proposed by the European Working Group on Sarcopenia in Older People (EWGSOP).
Methods: PubMed and Dialog databases were searched (January 2000–October 2013) using pre-defined search terms. Prevalence studies and intervention studies investigating muscle mass plus strength or function outcome measures using the EWGSOP definition of sarcopenia, in well-defined populations of adults aged ≥50 years were selected.
Results: prevalence of sarcopenia was, with regional and age-related variations, 1–29% in community-dwelling populations, 14–33% in long-term care populations and 10% in the only acute hospital-care population examined. Moderate quality evidence suggests that exercise interventions improve muscle strength and physical performance. The results of nutrition interventions are equivocal due to the low number of studies and heterogeneous study design. Essential amino acid (EAA) supplements, including ∼2.5 g of leucine, and β-hydroxy β-methylbutyric acid (HMB) supplements, show some effects in improving muscle mass and function parameters. Protein supplements have not shown consistent benefits on muscle mass and function.
Conclusion: prevalence of sarcopenia is substantial in most geriatric settings. Well-designed, standardised studies evaluating exercise or nutrition interventions are needed before treatment guidelines can be developed. Physicians should screen for sarcopenia in both community and geriatric settings, with diagnosis based on muscle mass and function. Supervised resistance exercise is recommended for individuals with sarcopenia. EAA (with leucine) and HMB may improve muscle outcomes.
PMCID: PMC4204661  PMID: 25241753
exercise intervention; nutrition intervention; prevalence; age-related; sarcopenia; older people
10.  Long-term Survival in Adults Aged 65 and Older With White Matter Hyperintensity: Association With Performance on the Digit Symbol Substitution Test 
Psychosomatic medicine  2013;75(7):10.1097/PSY.0b013e31829c1df2.
White matter hyperintensity (WMH) confers increased mortality risk in patients with cardiovascular diseases. However, little is known about differences in survival times among adults 65 years and older who have WMH and live in the community. To characterize the factors that may reduce mortality risk in the presence of WMH, measures of race, sex, ApoE4, neuroimaging, cardiometabolic, physiological and psychosocial characteristics were examined, with a particular focus on information processing as measured by the Digit Symbol Substitution Test(DSST).
Cox-proportional models were used to estimate mortality risks in a cohort of 3513 adults (74.8years, 58%women, 84%white) with WMH (0–9 points), DSST (0–90 points), risk factor assessment in 1992–94 and data on mortality and incident stroke to 2009 (median follow-up [range]:14.2[0.5–18.1]years).
WMH predicted a 48% greater mortality risk (age-adjusted hazard ratio (HR)[95% confidence interval(CI)] for WMH>3 points=1.48[1.35–1.62]). This association was attenuated after adjustment for DSST (HR[CI]: 1.38[1.27–1.51]) or lacunar infarcts (HR[CI]: 1.37[1.25,1.50]) but not after adjustment for other factors. The interaction between DSST and WMH was significant (p=0.011). In fully adjusted models stratified by WMH>3, participants with DSST>median had a 34% lower mortality risk among those with WMH>3 (n=532/1217) and a 28% lower mortality risk among those with WMH<3 (n=1364/2296), compared to participants with DSST
WMH is associated with increased long-term mortality risk in community-dwelling adults aged 65 and older. The increased risk is attenuated for those with higher DSST. Assessment of cognitive function with DSST may improve risk stratification of individuals with WMH.
PMCID: PMC3809761  PMID: 23886735
mortality; information processing; white matter hyperintensity
Games for Health Journal  2013;2(4):235-239.
Physical therapy, including exercise, improves gait and quality of life in Parkinson's disease (PD). Many programs promoting physical activity have generated significant short-term gains, but adherence has been a problem. A recent evidence-based analysis of clinical trials using physical therapy in PD patients produced four key treatment recommendations: cognitive movement strategies, physical capacity, balance training, and cueing. We have attempted to incorporate all four of these features together through a dance exercise program using the dance videogame “Dance Dance Revolution” (DDR) (Konami Digital Entertainment, El Segundo, CA).
Subjects and Methods
Sixteen medically stable participants with mild to moderate PD were given the opportunity to try DDR with supervision by a research staff member. Feedback about the advantages and disadvantages of DDR as a form of physical activity was elicited through focus groups using the nominal group technique.
Of 21 advantages and 17 disadvantages elicited, the most frequently cited advantages were “fun” and “easy to use,” followed by “improves balance or coordination,” “challenging,” and “full body aerobic activity.” Common concerns were the distracting or confusing interface, cost, and possible technical issues.
Interactive dance exercise was appealing to participants with PD and may help promote adherence to physical activity. Concerns regarding familiarity with the technology may be addressed with simplification of the interface or additional training for participants. Results support a larger longitudinal study of DDR in PD.
PMCID: PMC3833379  PMID: 24761325
Several consensus groups have previously published operational criteria for sarcopenia, incorporating lean mass with strength and/or physical performance. The purpose of this manuscript is to describe the prevalence, agreement, and discrepancies between the Foundation for the National Institutes of Health (FNIH) criteria with other operational definitions for sarcopenia.
The FNIH Sarcopenia Project used data from nine studies including: Age, Gene and Environment Susceptibility-Reykjavik Study; Boston Puerto Rican Health Study; a series of six clinical trials from the University of Connecticut; Framingham Heart Study; Health, Aging, and Body Composition Study; Invecchiare in Chianti; Osteoporotic Fractures in Men Study; Rancho Bernardo Study; and Study of Osteoporotic Fractures. Participants included in these analyses were aged 65 and older and had measures of body mass index, appendicular lean mass, grip strength, and gait speed.
The prevalence of sarcopenia and agreement proportions was higher in women than men. The lowest prevalence was observed with the FNIH criteria (1.3% men and 2.3% women) compared with the International Working Group and the European Working Group for Sarcopenia in Older Persons (5.1% and 5.3% in men and 11.8% and 13.3% in women, respectively). The positive percent agreements between the FNIH criteria and other criteria were low, ranging from 7% to 32% in men and 5% to 19% in women. However, the negative percent agreement were high (all >95%).
The FNIH criteria result in a more conservative operational definition of sarcopenia, and the prevalence was lower compared with other proposed criteria. Agreement for diagnosing sarcopenia was low, but agreement for ruling out sarcopenia was very high. Consensus on the operational criteria for the diagnosis of sarcopenia is much needed to characterize populations for study and to identify adults for treatment.
PMCID: PMC3991139  PMID: 24737561
Muscle; Sarcopenia; Lean mass.
This analysis sought to determine the associations of the Foundation for the National Institutes of Health Sarcopenia Project criteria for weakness and low lean mass with likelihood for mobility impairment (gait speed ≤ 0.8 m/s) and mortality. Providing validity for these criteria is essential for research and clinical evaluation.
Among 4,411 men and 1,869 women pooled from 6 cohort studies, 3-year likelihood for incident mobility impairment and mortality over 10 years were determined for individuals with weakness, low lean mass, and for those having both. Weakness was defined as low grip strength (<26kg men and <16kg women) and low grip strength-to-body mass index (BMI; kg/m2) ratio (<1.00 men and <0.56 women). Low lean mass (dual-energy x-ray absorptiometry) was categorized as low appendicular lean mass (ALM; <19.75kg men and <15.02kg women) and low ALM-to-BMI ratio (<0.789 men and <0.512 women).
Low grip strength (men: odds ratio [OR] = 2.31, 95% confidence interval [CI] = 1.34–3.99; women: OR = 1.99, 95% CI 1.23–3.21), low grip strength-to-BMI ratio (men: OR = 3.28, 95% CI 1.92–5.59; women: OR = 2.54, 95% CI 1.10–5.83) and low ALM-to-BMI ratio (men: OR = 1.58, 95% CI 1.12–2.25; women: OR = 1.81, 95% CI 1.14–2.87), but not low ALM, were associated with increased likelihood for incident mobility impairment. Weakness increased likelihood of mobility impairment regardless of low lean mass. Mortality risk patterns were inconsistent.
These findings support our cut-points for low grip strength and low ALM-to-BMI ratio as candidate criteria for clinically relevant weakness and low lean mass. Further validation in other populations and for alternate relevant outcomes is needed.
PMCID: PMC3991140  PMID: 24737560
Muscle; Sarcopenia; Mobility; Impairment.
Low lean mass is potentially clinically important in older persons, but criteria have not been empirically validated. As part of the FNIH (Foundation for the National Institutes of Health) Sarcopenia Project, this analysis sought to identify cutpoints in lean mass by dual-energy x-ray absorptiometry that discriminate the presence or absence of weakness (defined in a previous report in the series as grip strength <26kg in men and <16kg in women).
In pooled cross-sectional data stratified by sex (7,582 men and 3,688 women), classification and regression tree (CART) analysis was used to derive cutpoints for appendicular lean body mass (ALM) that best discriminated the presence or absence of weakness. Mixed-effects logistic regression was used to quantify the strength of the association between lean mass category and weakness.
In primary analyses, CART models identified cutpoints for low lean mass (ALM <19.75kg in men and <15.02kg in women). Sensitivity analyses using ALM divided by body mass index (BMI: ALMBMI) identified a secondary definition (ALMBMI <0.789 in men and ALMBMI <0.512 in women). As expected, after accounting for study and age, low lean mass (compared with higher lean mass) was associated with weakness by both the primary (men, odds ratio [OR]: 6.9 [95% CI: 5.4, 8.9]; women, OR: 3.6 [95% CI: 2.9, 4.3]) and secondary definitions (men, OR: 4.3 [95% CI: 3.4, 5.5]; women, OR: 2.2 [95% CI: 1.8, 2.8]).
ALM cutpoints derived from a large, diverse sample of older adults identified lean mass thresholds below which older adults had a higher likelihood of weakness.
PMCID: PMC3991141  PMID: 24737559
Muscle; Sarcopenia; Cutpoints.
Low muscle mass and weakness are common and potentially disabling in older adults, but in order to become recognized as a clinical condition, criteria for diagnosis should be based on clinically relevant thresholds and independently validated. The Foundation for the National Institutes of Health Biomarkers Consortium Sarcopenia Project used an evidence-based approach to develop these criteria. Initial findings were presented at a conference in May 2012, which generated recommendations that guided additional analyses to determine final recommended criteria. Details of the Project and its findings are presented in four accompanying manuscripts.
The Foundation for the National Institutes of Health Sarcopenia Project used data from nine sources of community-dwelling older persons: Age, Gene/Environment Susceptibility-Reykjavik Study, Boston Puerto Rican Health Study, a series of six clinical trials, Framingham Heart Study, Health, Aging, and Body Composition, Invecchiare in Chianti, Osteoporotic Fractures in Men Study, Rancho Bernardo Study, and Study of Osteoporotic Fractures. Feedback from conference attendees was obtained via surveys and breakout groups.
The pooled sample included 26,625 participants (57% women, mean age in men 75.2 [±6.1 SD] and in women 78.6 [±5.9] years). Conference attendees emphasized the importance of evaluating the influence of body mass on cutpoints. Based on the analyses presented in this series, the final recommended cutpoints for weakness are grip strength <26kg for men and <16kg for women, and for low lean mass, appendicular lean mass adjusted for body mass index <0.789 for men and <0.512 for women.
These evidence-based cutpoints, based on a large and diverse population, may help identify participants for clinical trials and should be evaluated among populations with high rates of functional limitations.
PMCID: PMC3991146  PMID: 24737557
Aging; Sarcopenia; Muscle; Outcomes; Weakness.
Weakness is common and contributes to disability, but no consensus exists regarding a strength cutpoint to identify persons at high risk. This analysis, conducted as part of the Foundation for the National Institutes of Health Sarcopenia Project, sought to identify cutpoints that distinguish weakness associated with mobility impairment, defined as gait speed less than 0.8 m/s.
In pooled cross-sectional data (9,897 men and 10,950 women), Classification and Regression Tree analysis was used to derive cutpoints for grip strength associated with mobility impairment.
In men, a grip strength of 26–32 kg was classified as “intermediate” and less than 26 kg as “weak”; 11% of men were intermediate and 5% were weak. Compared with men with normal strength, odds ratios for mobility impairment were 3.63 (95% CI: 3.01–4.38) and 7.62 (95% CI 6.13–9.49), respectively. In women, a grip strength of 16–20 kg was classified as “intermediate” and less than 16 kg as “weak”; 25% of women were intermediate and 18% were weak. Compared with women with normal strength, odds ratios for mobility impairment were 2.44 (95% CI 2.20–2.71) and 4.42 (95% CI 3.94–4.97), respectively. Weakness based on these cutpoints was associated with mobility impairment across subgroups based on age, body mass index, height, and disease status. Notably, in women, grip strength divided by body mass index provided better fit relative to grip strength alone, but fit was not sufficiently improved to merit different measures by gender and use of a more complex measure.
Cutpoints for weakness derived from this large, diverse sample of older adults may be useful to identify populations who may benefit from interventions to improve muscle strength and function.
PMCID: PMC3991145  PMID: 24737558
Muscle; Sarcopenia; Grip strength; Physical function; Gait speed.
Aging is associated with a progressive loss of muscle mass and strength and a decline in neurophysiological functions. Age-related neuromuscular junction (NMJ) plays a key role in musculoskeletal impairment that occurs with aging. However, whether changes in the NMJ precede or follow the decline of muscle mass and strength remains unresolved. Many factors such as mitochondrial dysfunction, oxidative stress, inflammation, changes in the innervation of muscle fibers, and mechanical properties of the motor units probably perform an important role in NMJ degeneration and muscle mass and strength decline in late life. This review addresses the primary events that might lead to NMJ dysfunction with aging, including studies on biomarkers, signaling pathways, and animal models. Interventions such as caloric restriction and exercise may positively affect the NMJ through this mechanism and attenuate the age-related progressive impairment in motor function.
PMCID: PMC4127816  PMID: 25157231
aging; denervation; motor unit; neuromuscular junction; sarcopenia
Journal of the American Geriatrics Society  2013;61(5):10.1111/jgs.12211.
Background and Objectives
White matter hyperintensities (WMH) on brain MRI are associated with cognitive and mobility impairment in older adults. We examined whether WMH in tracts in older adults with mobility impairment are linked to outcomes of gait rehabilitation interventions.
A 12-week randomized controlled single-blind trial.
University-based mobility research laboratory.
Ambulatory adults aged 65 and older with mobility impairment.
A conventional gait intervention focusing on walking, endurance, balance, and strength (WEBS, n=21) compared to a task-oriented intervention focused on timing and coordination of gait (TC, n=23).
We measured self-paced gait speed over an instrumented walkway, pre and post intervention, and quantified WMH and brain volumes on pre-intervention brain MRI using an automated segmentation process. We overlaid a white matter tract atlas on the segmented images to measure tract WMH volumes and normalized WMH volumes to total brain volume. Aggregate WMH volumes in all white matter tracts and individual WMH volumes in specific longitudinal tracts (the superior longitudinal fasciculus, inferior longitudinal fasciculus and the fronto-occipital fasciculus) and cingulum were obtained.
Gait speed gains in the TC group were of the same magnitude, independent of the WMH volume measures in all except the cingulum. However, in the WEBS group, gain in gait speed was smaller with greater overall tract WMH volumes (P<0.001) and with greater WMH volume in the three longitudinal tracts (P< 0.001 to 0.025).
Gains in gait speed with two types of gait rehabilitation are associated with individual differences in WMH. Task-oriented therapy that targets timing and coordination of gait may particularly benefit older adults with WMH in brain tracts that influence gait and cognition.
PMCID: PMC3874589  PMID: 23590257
Journal of General Internal Medicine  2012;27(11):1467-1474.
Hospital readmission within thirty days is common among Medicare beneficiaries, but the relationship between rehospitalization and subsequent mortality in older adults is not known.
To compare one-year mortality rates among community-dwelling elderly hospitalized Medicare beneficiaries who did and did not experience early hospital readmission (within 30 days), and to estimate the odds of one-year mortality associated with early hospital readmission and with other patient characteristics.
A cohort study of 2133 hospitalized community-dwelling Medicare beneficiaries older than 64 years, who participated in the nationally representative Cost and Use Medicare Current Beneficiary Survey between 2001 and 2004, with follow-up through 2006.
One-year mortality after index hospitalization discharge.
Three hundred and four (13.7 %) hospitalized beneficiaries had an early hospital readmission. Those with early readmission had higher one-year mortality (38.7 %) than patients who were not readmitted (12.1 %; p < 0.001). Early readmission remained independently associated with mortality after adjustment for sociodemographic factors, health and functional status, medical comorbidity, and index hospitalization-related characteristics [HR (95 % CI) 2.97 (2.24-3.92)]. Other patient characteristics independently associated with mortality included age [1.03 (1.02-1.05) per year], low income [1.39 (1.04-1.86)], limited self-rated health [1.60 (1.20-2.14)], two or more recent hospitalizations [1.47 (1.01-2.15)], mobility difficulty [1.51 (1.03-2.20)], being underweight [1.62 (1.14-2.31)], and several comorbid conditions, including chronic lung disease, cancer, renal failure, and weight loss. Hospitalization-related factors independently associated with mortality included longer length of stay, discharge to a skilled nursing facility for post-acute care, and primary diagnoses of infections, cancer, acute myocardial infarction, and heart failure.
Among community-dwelling older adults, early hospital readmission is a marker for notably increased risk of one-year mortality. Providers, patients, and families all might respond profitably to an early readmission by reviewing treatment plans and goals of care.
Electronic supplementary material
The online version of this article (doi:10.1007/s11606-012-2116-3) contains supplementary material, which is available to authorized users.
PMCID: PMC3475824  PMID: 22692634
readmission; mortality; older adults; care transitions
Background and Purpose
Mobility disability is a serious and frequent adverse health outcome associated with aging. Early identification of individuals at risk for mobility disability is important if interventions to prevent disability are to be instituted. The objectives of this prospective study were to: 1) determine the magnitude of stance time variability (STV) that discriminates individuals who currently have mobility disability (prevalent mobility disability) and 2) determine the magnitude of STV that predicts a new onset of mobility disability at one year (incident mobility disability).
552 community-dwelling older adults were evaluated as part of the Cardiovascular Health Study, a longitudinal cohort study. Stance time, in milliseconds (ms), was determined from 2 passes on a 4-meter computerized walkway at self-selected walking speed, and STV was defined as the standard deviation (SD) from approximately 12 individual steps. Mobility disability was defined as self-reported difficulty walking a half mile. Receiver operating characteristic (ROC) curves were plotted to determine an optimal cutoff value for stance time variability for prevalent and incident mobility disability, and the area under the ROC curve was computed.
The optimal cut-off score for STV (maximizing sensitivity and specificity) for prevalent mobility disability was 0.037 sec(sensitivity = 65%, specificity = 65%, AUC = 0.70) and for incident 1 year mobility disability was 0.034 sec(sensitivity = 61%, specificity = 60%, AUC = 0.65). The use of likelihood ratios demonstrated a gradient of risk across values of STV, with mobility risk increasing as values of STV increased.
Discussion and Conclusion
Values of STV may be useful in identifying older adults with mobility disability and at risk for future disability. We recommend the more conservative estimate for identifying risk, STV=0.034 s, which maximizes the sensitivity and minimizes false negatives. The relatively modest values on the validity indices could possibly be improved by increasing the reliability of the measurement of STV. Clinicians should interpret the cut-off values liberally and use STV in conjunction with other measures until further work is completed to validate STV as an indicator of mobility disability.
PMCID: PMC3349774  PMID: 22314273
Gait variability; Disability; Sensitivity; Specificity; Older Adults
To examine whether deficient B12 status or low serum B12 levels are associated with worse sensory and motor peripheral nerve function in older adults.
Health, Aging and Body Composition Study.
Two thousand two hundred eighty-seven adults aged 72–83 years [mean age: 76.5 ± 2.9 years; 51.4% female; 38.3% black].
Low serum B12 was defined based solely on serum B12 of <260 pmol/L, whereas deficient B12 status was defined as B12 <260 pmol/L, methylmalonic acid [MMA] >271 nmol/L and MMA >2-methylcitrate. Peripheral nerve function was assessed by peroneal nerve conduction amplitude and velocity [NCV] (motor); 1.4g/10g monofilament detection; average vibration threshold detection; and peripheral neuropathy symptoms [numbness; aching/burning pain] (sensory).
B12 deficient status was found in 7.0% and an additional 10.1% had low serum B12 levels. B12 deficient status was associated with greater insensitivity to light (1.4g) touch (OR: 1.50; 95% CI: [1.06, 2.13]) and worse NCV [42.3 m/s vs. 43.5 m/s] (β =−1.16; p=0.01), after multivariable adjustment for demographics, lifestyle factors, and health conditions. Associations were consistent for the alternative definition using low serum B12 only. No significant associations were found for deficient B12 status or the alternative low serum B12 definition and vibration detection, nerve conduction amplitude, or peripheral neuropathy symptoms.
Poor B12 (deficient B12 status and low serum B12) is associated with worse sensory and motor peripheral nerve function. Nerve function impairments may lead to physical function declines and disability in older adults, suggesting that prevention and treatment of low B12 levels may be important to evaluate.
PMCID: PMC3376015  PMID: 22690982
low B12; deficient B12; sensory peripheral nerve function; motor nerve conduction; older adults
Low vitamin B12 and high homocysteine (Hcy) levels are common in older adults and may be associated with worse neurological function. The aim of this study is to determine whether changes in B12 or Hcy levels are associated with longitudinal changes in peripheral nerve function and clinical neurological signs and symptoms.
Participants aged 60 years and older at baseline (n = 678; 72.2 ± 6.2 years; 43.5% male) were from the InCHIANTI Study. Low B12 (<260 pmol/L) and high Hcy (≥13 μmol/L) were measured at baseline and 3-year follow-up. Neurological function was assessed by peroneal nerve conduction amplitude (compound motor action potential) and velocity, neurological examination, and peripheral neuropathy symptoms at baseline, 3-year, and 6-year follow-up.
At baseline, 43.8% had low B12 levels and 58.6% had high Hcy levels. Over 6 years, 12.4% declined to poor compound motor action potential (<1 mV) and 42.1% declined to poor nerve conduction velocity (<40 m/s). In mixed models analyses, sustained high Hcy was associated with worse compound motor action potential compared with sustained normal Hcy (p = .04), adjusting for demographics, diabetes, and folate level. Participants whose Hcy level became high at follow-up were more likely to become unable to detect monofilament at 6-year follow-up compared with those with sustained normal Hcy (odds ratio: 5.4; 95% CI: 1.5–19.0), adjusting for demographics, diabetes, body mass index, and peripheral arterial disease. There was no association with vitamin B12 level or with symptoms.
High Hcy may be associated with worse sensory and motor peripheral nerve function. Because poor nerve function has been associated with lower strength and physical performance, these results have important implications for disability in older adults.
PMCID: PMC3326240  PMID: 22156506
Vitamin B12; Homocysteine; Peripheral nerve function; Neurological signs
Age and Ageing  2011;41(1):58-64.
Background: slower gait in older adults is related to smaller volume of the prefrontal area (PFAv). The pathways underlying this association have not yet been explored. Understanding slowing gait could help improve function in older age. We examine whether the association between smaller PFAv and slower gait is explained by lower performance on numerous neuropsychological tests.
Hypothesis: we hypothesise that slower information processing explains this association, while tests of language or memory will not.
Methods: data on brain imaging, neuropsychological tests (information processing speed, visuospatial attention, memory, language, mood) and time to walk 15 feet were obtained in 214 adults (73.3 years, 62% women) free from stroke and dementia. Covariates included central (white matter hyperintensities, vision) and peripheral contributors of gait (vibration sense, muscle strength, arthritis, body mass index), demographics (age, race, gender, education), as well as markers of prevalent vascular diseases (cardiovascular disease, diabetes and ankle arm index).
Results: in linear regression models, smaller PFAv was associated with slower time to walk independent of covariates. This association was no longer significant after adding information processing speed to the model. None of the other neuropsychological tests significantly attenuated this association.
Conclusions: we conclude that smaller PFAv may contribute to slower gait through slower information processing. Future longitudinal studies are warranted to examine the casual relationship between focal brain atrophy with slowing in information processing and gait.
PMCID: PMC3234076  PMID: 21965414
prefrontal volume; gait speed; information processing; elderly

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