Allon Goldberg

Adaptive evolution of cytochrome c oxidase subunit VIII in anthropoid primates

Cytochrome c oxidase (COX) is a 13-subunit protein complex that catalyzes the last step in mitochondrial electron transfer in mammals. Of the 10 subunits encoded by nuclear DNA (three are mtDNA products), some are expressed as tissue- and/or development-specific isoforms. For COX subunit VIII, previous work showed that expression of the contractile muscle-specific isoform gene, COX8H, is absent in humans and Old World monkeys, and the other isoform gene, COX8L, is expressed ubiquitously. Here, we show that COX8H is transcribed in most primate clades, but its expression is absent in catarrhines, that is, in Old World monkeys and hominids (apes, including humans), having become a pseudogene in the stem of the catarrhines. The ubiquitously expressed isoform, COX8L, underwent nonsynonymous rate acceleration and elevation in the ratio of nonsynonymous/synonymous changes in the stem of anthropoid primates (New World monkeys and catarrhines), possibly setting the stage for loss of the heart-type (H) isoform. The most rapidly evolving region of VIII-L is one that interacts with COX I, suggesting that the changes are functionally coadaptive. Because accelerated rates of nonsynonymous substitutions in anthropoids such as observed for COX8L are also shown by genes for at least 13 other electron transport chain components, these encoded amino acid replacements may be viewed as part of a series of coadaptive changes that optimized the anthropoid biochemical machinery for aerobic energy metabolism. We argue that these changes were linked to the evolution of an expanded neocortex in anthropoid primates.

The short version of the Activities-specific Balance Confidence (ABC) scale: Its validity, reliability, and relationship to balance impairment and falls in older adults

A shortened version of the ABC 16-item scale (ABC-16), the ABC-6, has been proposed as an alternative balance confidence measure. We investigated whether the ABC-6 is a valid and reliable measure of balance confidence and examined its relationship to balance impairment and falls in older adults. Thirty-five community-dwelling older adults completed the ABC-16, including the 6 questions of the ABC-6. They also completed the following clinical balance tests: unipedal stance time (UST), functional reach (FR), Timed Up and Go (TUG), and maximum step length (MSL). Participants reported 12-month falls history. Balance confidence on the ABC-6 was significantly lower than on the ABC-16, however scores were highly correlated. Fallers reported lower balance confidence than non-fallers as measured by the ABC-6 scale, but confidence did not differ between the groups with the ABC-16. The ABC-6 significantly correlated with all balance tests assessed and number of falls. The ABC-16 significantly correlated with all balance tests assessed, but not with number of falls. Test-retest reliability for the ABC-16 and ABC-6 was good to excellent. The ABC-6 is a valid and reliable measure of balance confidence in community-dwelling older adults, and shows stronger relationships to falls than does the ABC-16. The ABC-6 may be a more useful balance confidence assessment tool than the ABC-16.

The five-times-sit-to-stand test: validity, reliability and detectable change in older females

Background and aims: The five-timessit- to-stand test (FTSST) is a physical performance test commonly-used in clinical geriatric studies. The relationship between FTSST times and dynamic balance has not been widely investigated in older adults. The main objective of this study was to evaluate the validity of the FTSST as a measure of dynamic balance in older adults. A second objective was to quantify relative and absolute reliability, as well as minimum detectable change (MDC) of the FTSST in older adults. Methods: Twenty-nine females (mean age, 73.6 years) performed two trials of the FTSST, timed up and go (TUG), and functional reach (FR) tests. Validity of the FTSST as a measure of dynamic balance was evaluated by quantifying strength of relationships between the FTSST and two measures of dynamic balance, TUG and FR, using Pearson’s correlation coefficient. Measures of relative [intraclass correlation coefficient (ICC)] and absolute [standard error of measurement (SEM)] reliability, as well as the MDC at the 95% confidence level (MDC95) were computed for the FTSST. Results: The Pearson’s correlation coefficient between FTSST and TUG (r=0.64, p<0.001) indicates that FTSST is a valid measure of dynamic balance and functional mobility in older adults. The ICC2,1 of 0.95 is indicative of excellent relative reliability of the FTSST. SEM was 0.9 seconds and MDC95 was 2.5 seconds for the FTSST. SEM (6.3% of mean FTSST) and MDC (17.5% of mean FTSST) percent values were low. Conclusions: The FTSST is a valid measure of dynamic balance and functional mobility in older adults. The high ICC and low SEM and SEM% suggest excellent relative and absolute reliability and reproducibility of the FTSST in older adults. Change in FTSST performance should exceed 2.5 seconds to be considered real change beyond measurement error.

Decreased Muscle Strength Relates to Self-Reported Stooping, Crouching, or Kneeling Difficulty in Older Adults

Background Bending down and kneeling are fundamental tasks of daily living, yet nearly a quarter of older adults report having difficulty performing or being unable to perform these movements. Older adults with stooping, crouching, or kneeling (SCK) difficulty have demonstrated an increased fall risk. Strength (force-generating capacity) measures may be useful for determining both SCK difficulty and fall risk. Objective The purposes of this study were: (1) to examine muscle strength differences in older adults with and without SCK difficulty and (2) to examine the relative contributions of trunk and leg muscle strength to SCK difficulty. Design This was a cross-sectional observational study. Methods Community-dwelling older adults (age [X̅±SD]=75.5±6.0 years) with SCK difficulty (n=27) or without SCK difficulty (n=21) were tested for leg and trunk strength and functional mobility. Isometric strength at the trunk, hip, knee, and ankle also was normalized by body weight and height. Results Compared with older adults with no SCK difficulty, those with SCK difficulty had significant decreases in normalized trunk extensor, knee extensor, and ankle dorsiflexor and plantar-flexor strength. In 2 separate multivariate analyses, raw ankle plantar-flexor strength (odds ratio [OR]=0.97, 95% confidence interval [CI]=0.95–0.99) and normalized knee extensor strength (OR=0.61, 95% CI=0.44–0.82) were significantly associated with SCK difficulty. Stooping, crouching, and kneeling difficulty also correlated with measures of functional balance and falls. Limitations Although muscle groups that were key to rising from SCK were examined, there are other muscle groups that may contribute to safe SCK performance. Conclusions Decreased muscle strength, particularly when normalized for body size, predicts SCK difficulty. These data emphasize the importance of strength measurement at multiple levels in predicting self-reported functional impairment.

Minimum detectable change for single-leg-stance-time in older adults.

INTRODUCTION Knowledge of real change values for clinical balance measures can guide clinicians and researchers in interpretation of change scores to evaluate the effectiveness of therapeutic interventions. We are not aware of studies that have reported minimum change values for single-leg-stance-time (SLST) in community-dwelling older adults. A measure of absolute reliability, the standard error of measurement (SEM), can be used to compute minimum detectable change (MDC), a clinically useful indicator of change in performance exceeding that attributable to measurement error. The purpose of this study was to quantify MDC for SLST in community-dwelling older adults. METHODS Twenty-five adults (60-89 years) performed repeated trials of SLST. Relative and absolute reliability for SLST were quantified using the intraclass correlation coefficient and SEM. The MDC was computed from the SEM. RESULTS SEM was 8.7 s and MDC at the 95% confidence level was 24.1 s for SLST. SLST exhibited large measurement error (40.8%) and high minimum change (113.1%) percent values. CONCLUSION Change in SLST performance should exceed 24.1 s to be considered real change. SLST exhibits poor absolute reliability and appears unlikely to be sensitive to detecting change in performance in geriatric clinical settings and research studies.

Measurement error and minimum detectable change in 4-meter gait speed in older adults

Background and aims: Gait speed is a commonly-used assessment and outcomes measure in geriatric clinical and research settings. Although relative reliability of usual gait speed has been well studied in community-dwelling older adults, less emphasis has been placed on a measure of absolute reliability (the standard error of measurement [SEM]), and on an associated clinically relevant index of real change in gait speed, minimum detectable change (MDC). The purpose of this study was to quantify measurement error and MDC for usual gait speed over 4 meters in community-dwelling older adults ambulating at intermediate and fast speeds. Methods: Community-dwelling older adults ambulating at intermediate gait speed (IGS), (n=15, mean age 74.2 yrs) and fast gait speed (FGS), (n=15, mean age 72.1) were included in this study. Participants performed two trials of gait speed over a distance of 4 meters. SEM and MDC at the 95% confidence level (MDC95) were computed for the IGS and FGS groups. Results: Mean gait speed was 85.4 cm/s (IGS) and 129.9 cm/s (FGS). Measurement error (<5% of mean gait speed) and minimum detectable change (<13% of mean gait speed) were low in both groups. MDC95 was computed as 10.8 cm/s and 14.4 cm/s for the IGS and FGS groups, respectively. Conclusions: To be considered real change beyond the bounds of measurement error, change in 4-meter gait speed should exceed 10.8 cm/s (for intermediate speed ambulators) or 14.4 cm/s (for fast speed ambulators). Low measurement error in assessing 4-meter gait speed in community-dwelling older adults suggests that gait speed assessed over short distances has excellent reproducibility across trials. Low minimum change values suggest that 4-meter gait speed may be responsive and sensitive to change.

Standing Balance and Trunk Position Sense in Impaired Glucose Tolerance (IGT)-Related Peripheral Neuropathy

Type 2 diabetes mellitus (T2DM) and pre-diabetes or impaired glucose tolerance (IGT) affect a large segment of the population. Peripheral neuropathy (PN) is a common complication of T2DM, leading to sensory and motor deficits. While T2DM-related PN often results in balance- and mobility-related dysfunction which manifests as gait instability and falls, little is known about balance capabilities in patients who have evidence of PN related to IGT (IGT-PN). We evaluated patients with IGT-PN on commonly-used clinical balance and mobility tests as well as a new test of trunk position sense and balance impairment, trunk repositioning errors (TREs). Eight participants aged 50-72 years with IGT-PN, and eight age- and gender-matched controls underwent balance, mobility and trunk repositioning accuracy tests at a university neurology clinic and mobility research laboratory. Compared to controls, IGT-PN participants had as much as twice the magnitude of TREs and stood approximately half as long on the single leg balance test. People with IGT-PN exhibit deficits in standing balance and trunk position sense. Furthermore, there was a significant association between performance on commonly-used clinical balance and mobility tests, and electrophysiological and clinical measures of neuropathy in IGT-PN participants. Because IGT-related neuropathy represents the earliest stage of diabetic neuropathy, deficits in IGT-PN participants highlight the importance of early screening in the dysglycemic process for neuropathy and associated balance deficits.

The five-times-sit-to-stand-test (FTSST), the short version of the activities-specific balance confidence (ABC) scale, and fear of falling predict step execution time (SET) in older adults

Rapid stepping is a common strategy employed by older adults to avoid falls. The relative contributions of dynamic balance, balance confidence and fear of falling to SET, was investigated in older adults. Thirty-three community-dwelling older adults completed tests of SET as well as the FTSST, a test of motor performance associated with dynamic balance. Psychological indicators of balance-related confidence assessed were the ABC 6-item scale (ABC-6) and fear of falling. Mean SET was significantly slower in the fear of falling group than in the no fear of falling group (p<0.001). Correlational analysis indicated that poorer performance on the FTSST and lower balance confidence, were associated with slower time to execute a rapid step. A stepwise multiple regression model including the FTSST, ABC-6 score, and fear of falling as predictor variables, explained 58% of the variance in SET (p<0.001). The FTSST explained the largest proportion of the variance in SET (36%), followed by fear of falling (15%) and ABC-6 score (7%). These data show that the FTSST, ABC-6 score and fear of falling are significant and independent predictors of SET in older adults. Dynamic balance, balance confidence and fear of falling, may play important roles in executing rapid steps in older adults. Motor performance and psychological indicators of balance-related confidence appear to have crucial roles in SET in older adults.

Deficits in stepping response time are associated with impairments in balance and mobility in people with Huntington disease

Huntington disease (HD) is a disorder characterized by chorea, dystonia, bradykinesia, cognitive decline and psychiatric comorbidities. Balance and gait impairments, as well as falls, are common manifestations of the disease. The importance of compensatory rapid stepping to maintain equilibrium in older adults is established, yet little is known of the role of stepping response times (SRTs) in balance control in people with HD. SRTs and commonly-used clinical measures of balance and mobility were evaluated in fourteen symptomatic participants with HD, and nine controls at a university mobility research laboratory. Relative and absolute reliability, as well as minimal detectable change in SRT were quantified in the HD participants. HD participants exhibited slower SRTs and poorer dynamic balance, mobility and motor performance than controls. HD participants also reported lower balance confidence than controls. Deficits in SRT were associated with low balance confidence and impairments on clinical measures of balance, mobility, and motor performance in HD participants. Measures of relative and absolute reliability indicate that SRT is reliable and reproducible across trials in people with HD. A moderately low percent minimal detectable change suggests that SRT appears sensitive to detecting real change in people with HD. SRT is impaired in people with HD and may be a valid and objective marker of disease progression.

Validity, reliability and minimum detectable change of the maximum step length test in people with stroke.

Stroke is a significant cause of deficits in balance, mobility and disability. Although tests of stepping speed are associated with balance performance after stroke, relationships between clinical tests of stepping distance and balance performance have not been investigated in people with stroke. A validated test of stepping distance and balance in older adults (the maximum step length [MSL] test), and two clinical measures associated with balance in people with stroke (the five-times-sit-to-stand test [FTSST] and gait speed) were evaluated in nineteen independent community-dwelling people with chronic stroke. There were strong relationships between MSL and performance on the clinical balance measures (Pearsons r 0.69 to -0.88), suggesting that MSL is a valid measure of balance after stroke. Test-retest reliability coefficients were excellent for the MSL tests (ICC both limbs; 0.98). Standard error of measurement expressed as a percentage of mean MSL was computed as 5.6% (hemiparetic leg) and 5.4% (unaffected leg), indicative of low levels of measurement error and excellent absolute reliability of the MSL test in people with stroke. Minimum detectable change expressed as a percentage of mean MSL was low (14.9% to 15.4%), suggesting that MSL may be sensitive to detecting change in physical performance in people with stroke. Advantages of the MSL test are that it is easy to administer, requiring minimal training, equipment, time or space. These advantages, together with the validity of the MSL test, its excellent test-retest and absolute reliability, and its low minimum change percent value suggest that MSL may be a useful measure of balance capabilities in people with stroke.