Dimensions of physical frailty and cognitive function in older adults with amnestic mild cognitive impairment

Abstract

Objective

The objective of this study was to examine relationships between dimensions of physical frailty and severity of cognitive impairment in older adults with amnestic mild cognitive impairment (aMCI).

Patients and methods

The prevalence of physical frailty dimensions including slow gait speed, low physical activity, and low grip strength was examined among 201 sedentary older adults with aMCI. Associations between dimensions of physical frailty and severity of cognitive impairment, as measured with the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and individual dimensions of cognitive function were examined using multiple linear regression models.

Results

Greater than 50% of participants met physical frailty criteria on dimensions of slow gait speed, low physical activity and low grip strength. Slower gait speed was associated with elevated severity of cognitive impairment. Both gait speed and physical activity were associated with individual dimensions cognitive function.

Conclusions

Dimensions of physical frailty, particularly gait speed, were associated with severity of cognitive impairment, after adjusting for age, sex and age-related factors. Further studies are needed to investigate mechanisms and early intervention strategies that assist older adults with aMCI to maintain function and independence.

1. English version

1.1. Introduction

Older adults with both cognitive and physical impairments are at elevated risk for falls, disability, and institutionalization [56]. Mild cognitive impairment (MCI) is a transitional state less severe than dementia but beyond that of typical age-related cognitive changes [40]. There are two major sub-classifications of MCI, amnestic MCI (aMCI) and non-amnestic MCI (naMCI) [39]. aMCI involves impairment of cognitive dimensions specific to memory and attention, while naMCI is characterized by reduced function in cognitive domains other than memory [39,41]. Older adults with aMCI are at highest risk for developing Alzheimer’s disease (AD) [23]. A temporal relationship exists between declining cognitive function and declining physical function in older adults with AD [13]. Reduced physical function is evident prior to the onset of dementia [1,29,30,35], contributing to accelerated global decline and disability.

Older adults with MCI (amnestic and non-amnestic) demonstrate declining physical function including slower walking, reduced balance reactions and elevated risk for falling [32,34,38]. Physical frailty, a convergence of cumulative stress from multiple physiological systems, is also associated with increased incident falls, activities of daily living (ADL) dependence, hospitalization and disability [10,18,21,37,60]. Identification of physical frailty associated with severity of cognitive impairment is needed to develop early intervention and rehabilitation strategies aimed at assisting older adults in maintaining their health and independence.

A frailty index derived from the Cardiovascular Health Study includes the clinical presentation of three of five criteria: slow gait, low grip strength, low physical activity (PA), low energy, and unintentional weight loss [21]. More broadly defined, slowness, low PA, low strength, exhaustion, and body composition represent dimensions of physical frailty [5]. Of these dimensions slow gait speed, low PA and low grip strength have been reported to be predictive of cognitive impairment and incident disability in community-dwelling older adults [3,31,43,55,62]. Concurrent presentation of slow gait speed and cognitive impairment has been reported to be more strongly associated with the onset of dementia than either slow gait speed alone or cognitive impairment alone [57].

Although a relationship between physical frailty and cognitive function have been reported, severity of cognitive impairment has not been studied in relation to key aspects of physical frailty. The Alzheimer’s Disease Assessment Scale- Cognitive Subscale (ADAS-Cog) is associated with the rate of disease progression in older adults with mild to moderate AD [27,65], and has been shown to discriminate between very mild to mild dementia in addition to more advanced stages of AD [66], therefore, it may also be sensitive to reduced global cognitive function in individuals with aMCI.

In persons with aMCI, pathological mechanisms involved in AD may manifest as physical decline prior to the onset of dementia through alterations in memory, attention and executive function networks [12,15,16,54]. Alternatively, age and age-related conditions may contribute to concurrent decline of physiological systems via underlying mechanisms such as inflammation [19] and energetic pathways [49]. Early identification of relationships between physical frailty and severity of cognitive impairment are important for timely interventions aimed at slowing or reversing functional decline and disability in persons with aMCI.

The purpose of this study was two-fold, first, to describe the prevalence of three dimensions of physical frailty in older adults with aMCI, and, second, to examine whether aspects of physical frailty are associated with severity of cognitive impairment. We hypothesized that dimensions of physical frailty would be associated with severity of cognitive impairment and dimensions of cognitive function after adjusting for sex, age, and age-related conditions.

1.2. Method

This study involved analysis of baseline data from the Resources and Activities for Life-Long Independence (RALLI) study, a randomized controlled trial of psychosocial and exercise interventions for sedentary older adults with aMCI, who were enrolled between July 2007 and October 2009. Participants were volunteers living in independent retirement residences who reported mild memory problems. Participants enrolled in the study were age 70 and older, sedentary, and classified as having aMCI based on screening interviews and a consensus meeting of an expert panel. Study recruitment and screening consisted of:

• a phone screening;

• an in-home screening with a semi-structured interview and neuropsychological tests;

• an expert consensus panel of clinical psychologists.

Petersen criteria [39,40], using a combination of cognitive test scores, screening interview data, and consensus case review, were applied to identify persons with memory problems consistent with a clinical subtype of aMCI (single or multiple domain). Petersen criteria included:

• memory complaint;

• impaired memory for age and education;

• preserved general cognitive function;

• essentially preserved ADLs;

• no diagnosis of dementia.

Neuropsychological screening included:

• the Mini-Mental State Exam (MMSE) for global cognition [20];

• the Wechsler Memory Scale-Revised (WMS-R) Logical Memory I & II for immediate and delayed recall [59];

• the Clinical Dementia Rating (CDR) scale for severity rating of cognitive impairment [26].

Objective memory impairment was determined by: a score on the WMS-R Logical Memory tests that was 1 standard deviation below age- and education-adjusted norms [50], problems on memory recall items of the MMSE, and/or observed difficulty with everyday recall during the interview. Sedentary lifestyle was defined as less than 150 minutes of moderate-intensity exercise per week (over the past month) [36].

Potential participants were excluded if they:

• were unable to walk independently with an assistive device;

• were expecting to move away from the area;

• had a known terminal illness;

• were actively suicidal, hallucinating, or delusional;

• had been hospitalized within 12 months;

• had an uncontrolled chronic medical condition;

• were blind or deaf;

• or had a known central nervous system condition associated with dementia.

The local institutional review board approved all study procedures.

1.2.1. Physical frailty dimensions

Dimensions of physical frailty, adapted from Fried’s frailty index [21] included physical slowness (gait speed), low PA (self-report), and muscle weakness (grip strength). Gait speed was measured with an 8-foot timed walk at usual walking speed; usual gait speed (meters/second) and the better of two trials was used. Cut-points to define frail gait speed, stratified by sex and height, were ≤ 0.65 m/sec for women ≤ 159 cm tall and men ≤ 173 cm tall; and ≤ 0.76 m/sec for women > 159 cm tall and men > 173 cm tall.

PA was measured using the Physical Activity Scale for the Elderly (PASE), a self-report assessment of PA over the past week [58]. Cut-points to define frail PA were derived by calculating energy expenditure per week after assigning a metabolic equivalent (MET) to five PASE activity categories and multiplying by minutes completed per category. The activity categories represented walking, light recreation, moderate sports, strenuous sports, strength and endurance activities. Weighted usual MET levels stratified by age were used in accordance with the Centers for Disease Control and Prevention (CDC) and American College of Sports Medicine (ASCM) guidelines [2,25], and total Kcal/week were summed. The cutpints were < 383 Kcals/week for men and < 270 Kcals/week for women [21].

Grip strength was measured with a dominant hand maximum isometric grip strength (kg) test using a Jamar^® hydraulic hand dynamometer (Lafayette Instruments, Lafayette, IN); the average of two trials was calculated. Good reliability has been reported in older adults [53]. Frail grip strength cut-points were stratified by sex and BMI (kg/m²) [21]. Cut-points for women were ≤ 17 kg for BMI ≤ 23 kg/m², ≤ 17.3 kg for BMI ≤ 23–26 kg/m², ≤ 18 kg for BMI ≤ 26–29 kg/m², and ≤ 21 kg for BMI ≥ 29 kg/m². Cut-points for men were ≤ 29 kg for BMI ≤ 24 kg/m², ≤ 30 kg for BMI ≤ 24.1–26 kg/m², ≤ 30 kg for BMI ≤ 26.1–28 kg/m², and ≤ 32 kg for BMI ≥ 28 kg/m².

1.2.2. Cognitive function dimensions

Severity of cognitive impairment was measured with the ADAS-Cog. The ADAS-Cog scale contains 11 sub-items and has been widely used for assessing cognitive function in AD drug trials [45]. A higher ADAS-Cog score (0–60) is associated with greater disease severity in cross-sectional and longitudinal studies [51,65,66]. Attention and executive function were measured with the Trail Making A & B tests. The Trail Making part A (TMT-A) [42] a task of visual attention that involves connecting numbers 1–25 was used as a measure of attention [9]. The Trail Making part B (TMT-B) is an executive function task that measures complex visual scanning, speed, attention, and the ability to shift sets [24,42]. TMT-B is more difficult than TMT-A because of increased demands for motor speed and visual search [22]. Normative values have been reported for Trail Making A & B scores [64]. Memory was assessed using the WMS-R Logical Memory I (LMI) and the Word Recall sub-item of the ADAS-Cog. The WMS-R LMI [59] involves the immediate recall of a story read to the participant (score of 0–50). The ADAS-Cog Word Recall score is the number of words that the subject is able to recall, averaged over three trials (10 words/trial).

1.2.3. Covariates

Covariates known to influence both physical frailty and cognitive function were entered into multiple linear and logistic regression models. Covariates included age, sex, BMI, depressive symptoms, musculoskeletal comorbidity, and BMI. Age was entered as a continuous variable. Sex was coded male = 0 and female = 1. BMI was calculated using baseline weight and height (kg/m²) and entered as a continuous variable. Depressive symptoms, assessed using the Geriatric Depression Scale (GDS, range = 0–15), was entered as a continuous variable [63]. Musculoskeletal comorbidity, assessed using the Self-Administered Comorbidity Questionnaire (SCQ) [48], was entered as a dichotomous variable (no conditions = 0, one or more conditions = 1).

1.2.4. Data analysis

SPSS version 16.0 statistical software (SPSS, Inc., Chicago, IL) was utilized for data analysis. Frequencies and percentages were calculated for frail gait speed, frail PA, and frail grip strength using the cut-points described above. Multiple linear regression models were created to examine associations between dimensions of physical frailty (outcome variables) and cognitive function (explanatory variables). Continuous variables for physical frailty included usual gait speed (m/sec), the PASE score and grip strength (kg). Covariates in the gait speed model include age, sex, height, musculoskeletal comorbidity, and depression (GDS). Covariates in the PA model include age, sex, musculoskeletal comorbidity, and depression (GDS). Covariates in the grip strength model include age, sex, BMI, musculoskeletal comorbidity, and depression (GDS). Correlations and the variance inflation factor (VIF) for multi-collinearity were used to identify whether covariates were strongly correlated. Residual analysis for each multiple linear regression model included normal probability plots and scatter plots of standardized residuals. Model assumptions were adequately met for linearity, normality, independence of errors, and homoscedasticity of errors.

1.3. Results

Demographic, covariate, cognitive function, and physical frailty variables are summarized in Table 1. The initial sample was composed of 201 participants; however, due to episodic missing data between 173 and 201 cases were included in the multiple linear regression analyses. For example, some participants did not complete the Trail Making Tests due to vision problems. The mean MMSE was 26.3 (SD = 3.2) and all participants had a 0.5 CDR, consistent with classifications for aMCI [41]. The percent of participants that met criteria for the three dimensions of frailty were as follows: frail gait speed 57.3%, frail PA 58.2%, and frail grip strength 64.2% (Table 2).

Table 1.

Descriptive statistics.

	n	Mean (SD) or percent	Min	Max
Characteristics and covariates
Age, mean (SD)	201	84.2 (5.7)	70	104
Gender, % female	201	80.1%	–	–
Ethnicity, % Caucasian	201	91.0%	–	–
% HS education	201	97.5%	–	–
MMSE	201	26.3 (3.2)	18	30
% MSK comorbidity	201	74.1%	–	–
Geriatric Depression Scale (GDS)	199	2.48 (2.37)	0	12
Body mass index (BMI)	200	27.05 (5.07)	17.13	46.74
Dimensions of cognitive function
TMT-B (secs)	182	148 (70.3)	47	300*
TMT-A (secs)	189	55.9 (29.9)	21	264
Word recall	196	6.1 (1.4)	2.3	9.3
LM1	200	19.9 (7.4)	5	42
ADAS-Cog	198	8.0 (3.36)	0.67	19.33
Dimensions of physical frailty
Grip strength (kg)	192	38.12 (12.11)	5	102
Usual gait velocity (m/sec)	199	0.64 (0.18)	0.25	1.11
PASE	199	40.11 (29.1)	0	176.2

SD: standard deviation; HS Education: completed high school education; MSK comorbidity: musculoskeletal comorbidity; MMSE: Mini-Mental State Exam; TMT-A: Trail Making A; TMT-B: Trail Making B; LM1: Logical Memory 1; ADAS-Cog: Alzheimer’s Disease Assessment Scale-Cognitive Subscale; PASE: Physical Activity Scale for the Elderly.

^*8.0% (n = 16) of participants had the maximum TMT-B time of 300 seconds.

Table 2.

Percent of participants with dimensions of physical frailty.

Frailty dimension	n	Percent
Frail gait speed	199	57.3
Frail physical activity	199	58.2
Frail grip strength	198	64.2

1.3.1. Gait speed and cognitive function

Faster usual gait speed was significantly associated with better scores on the ADAS-Cog in the unadjusted model (β = −0.25, P = < 0.001) and this association remained statistically significant after adjusting for age, sex, musculoskeletal comorbidity and depression (β = −0.19, P = 0.008) (Table 3). Associations between faster usual gait speed and better performance on tests of cognitive dimensions were statistically significant for the TMT-A, TMT-B, Word Recall and LM1 (P = < 0.05). In summary, faster usual gait speed was associated with lower severity of cognitive impairment, as measured with the ADAS-Cog. In addition, faster usual gait speed was associated with better performance in cognitive dimensions of attention, executive function and immediate recall (Table 3).

Table 3.

Multiple regression models: associations between dimensions of physical frailty and cognitive function.

	Gait speed (m/sec)				PASE Score				Grip strength (kg)
	Unadjusted		Adjusteda		Unadjusted		Adjustedb		Unadjusted		Adjustedc
	β	P	β	P	β	P	β	P	β	P	β	P
ADAS-Cog	−0.25	< 0.001*	−0.19	0.008*	−0.18	0.01*	−0.10	0.18	−0.13	0.85	−0.05	0.40
TMT-A	−0.26	<0.001*	−0.23	0.001*	−0.15	0.17	−0.04	0.62	−0.05	0.50	−0.16	0.008*
TMT-B	−0.25	0.001*	−0.20	0.006*	−0.21	0.004*	−0.18	0.02*	−0.06	0.43	−0.04	0.46
Word Recall	−0.25	0.001	−0.18	0.02*	0.24	0.001*	0.17	0.02*	0.02	0.83	0.05	0.39
LM1	0.07	0.008*	0.14	0.04*	0.15	0.04*	0.13	0.06	0.13	0.86	−0.01	0.80

β: standardized coefficient; TMT-A: Trail Making A; TMT-B: Trail Making B; LM1: Logical Memory 1; ADAS-Cog: Alzheimer’s Disease Assessment Scale-Cognitive Subscale.

^*P < 0.05.

^aModel adjusted for age, sex, height, depressive symptoms (GDS), and musculoskeletal comorbidity.

^bModel adjusted for age, sex, depressive symptoms (GDS), and musculoskeletal comorbidity.

^cModel adjusted for age, sex, body mass index, depressive symptoms (GDS), and musculoskeletal comorbidity.

1.3.2. Physical activity and cognitive function

Higher PASE scores were associated with better performance on the ADAS-Cog in the unadjusted model (β = −0.18, P = 0.01), but this was no longer statistically significant after adjusting for age, sex, musculoskeletal comorbidity and depression (β = −0.10, P = 0.18). When examining associations between PASE scores and individual cognitive dimensions, there were statistically significant associations between higher PASE scores and better scores on the TMT-B and Word Recall in the unadjusted and adjusted models (P = < 0.05), as well as a trend between PASE and LM1 (Table 2). In summary, higher PA was not associated with severity of cognitive impairment after adjusting for covariates. However, associations between higher PA and better performance in the cognitive dimensions of memory and executive function were statistically significant and remained so after adjusting for covariates (Table 3).

1.3.3. Grip strength and cognitive function

Associations between grip strength and ADAS-Cog scores were not statistically significant in the unadjusted model (β = −0.02, P = 0.75) or after adjusting for covariates (β = −0.05, P = 0.40). When examining associations between grip strength and individual cognitive dimensions, the association between grip strength and TMT-A was statistically significant after adjusting for covariates (β = −0.16, P = 0.008), but there were no other statistically significant associations with other dimensions of cognitive function (Table 2). In summary, grip strength was not associated with severity of cognitive impairment. Grip strength was significantly associated with attention after adjusting for height, age, sex, musculoskeletal comorbidity and depression, but not with any other cognitive dimensions.

1.4 Discussion

In this study of sedentary older adults with aMCI, greater than 50% of participants were frail on dimensions of slow gait speed, low PA and low grip strength. Lower performance on dimensions of physical frailty was associated with worse performance on the ADAS-Cog, a measure of severity of cognitive impairment. In particular, slower usual gait speed was associated with elevated severity of cognitive impairment and worse performance within all dimension of memory, attention, and executive function, after adjusting for age, sex, and age-related covariates. Taken together, the results of this study provide support for a relationship between dimensions of physical frailty and severity of cognitive impairment in sedentary older adults with aMCI. Given that concurrent impairments in physical and cognitive domains accelerates functional decline and subsequent disability in older adults [28,57], these findings are clinically relevant for rehabilitation professionals when working with older adults with cognitive impairment.

In our study population, there was a high prevalence of slow gait speed, low PA and low grip strength. After adjusting for age and age-related covariates, associations between gait speed and severity of cognitive impairment remained. This was also true when examining dimensions of physical frailty in relation to individual cognitive dimensions. These findings suggest that factors other than age, sex and age-related factors account for associations between dimensions of physical frailty (slow gait and low PA) and lower cognitive function in older adults with aMCI.

Consistent with previous studies, our findings demonstrate associations between lower PA and lower executive function. In a cross-sectional study of healthy men and women, higher longterm PA levels were associated with higher executive function, but not with non-executive functions [6]. Physical dysfunction and executive dysfunction have also been implicated in elevated risk for dementia in community-dwelling older adults, including persons with aMCI [3,7,46,47]. Taken together, these results indicate that further research is warranted on PA as a preventive and rehabilitation strategy in persons with aMCI.

Our study showed that grip strength was associated with only attention (TMT-A), but found no relationship between grip strength and severity of cognitive impairment or other dimensions of cognitive function. In contrast, previous studies have reported a relationship between reduced grip strength and subsequent cognitive impairment [47], all-cause mortality [52,61], and greater AD pathology on autopsy [14]. It is plausible that grip strength is less sensitive for detecting general muscle strength deficits in early stages of cognitive decline, but becomes a more sensitive measure in individuals with a diagnosis of AD, especially with disease progression. A study by Boyle et al. (2009) tested muscle strength in nine muscle groups of older adults and reported a reduced risk for MCI and AD associated with better muscle strength [11]. Warranting further study on the presence and direction of this relationship, global cognitive decline preceded performance decline on grip strength and chair stands in older women in the Women’s Health Initiative Study [4].

Although the mechanisms underlying the relationship between physical frailty and cognitive function in older adults with aMCI remain unclear, several potential mechanisms related to AD pathology have been suggested. First, the slowing of gait prior to the onset of dementia may occur in conjunction with declining cognitive abilities, such as attention and perceptual speed for the planning and monitoring of physical performance [13]. Second, gray matter structural atrophy in the prefrontal cortex and hippocampal regions in association with slower walking speed has been reported [33,44]. Third, pathology not typically associated with AD, but instead associated with other dementia syndromes (e.g., Parkinson’s disease, vascular disease) may interfere with frontal-subcortial circuits [8,54]. For example, white matter hyperintensities (WMH) in the brain, attributed to vascular and cardiovascular disease, are associated with greater severity of cognitive impairment as well as physical frailty. Older adults with MCI and mild AD showed greater WMH in association with higher (worse) scores on the ADAS-Cog in cross-sectional and longitudinal studies [17]. Greater WMH burden has also been associated with worse performance in executive function, physical performance and falls in community-dwelling older adults [67,68]. Finally, pathological mechanisms associated with physical frailty, such as age and age-related conditions may contribute to concurrent decline of physiological systems via underlying mechanisms such as inflammation [19] and energetic pathways [49].

There are limitations to this study. The cross-sectional nature of this study does not allow for inference of causation; however, the results provide a basis for future research to examine mechanisms and causative relationships. There may be ceiling effects on measures of cognitive function in older adults with aMCI. Our participants were sedentary older adults with aMCI at baseline of a randomized clinical trial and our results are therefore generalizable only to older adults similar to our study population. Thus, more active, less cognitively impaired older adults may yield different associations between dimensions of physical frailty and cognitive function.

1.5 Conclusions

In this study of sedentary older adults with aMCI, dimensions of physical frailty were associated with severity of cognitive impairment and dimensions of cognitive function, after adjusting for age, sex, and age-related covariates. In particular, our study demonstrated that slower usual gait speed was associated with severity of cognitive impairment as measured with the ADAS-Cog. Further investigation is needed to address biological mechanisms and early intervention strategies that assist older adults with aMCI to maintain function and independence. Future research exploring the mechanisms that underlie associations between physical function and severity of cognitive impairment in older adults with aMCI may elucidate potential avenues for prevention and rehabilitation strategies.