Archives of Gerontology and Geriatrics 75 (2018) 20–27

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Archives of Gerontology and Geriatrics

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Full Length Article

Association of nutrition and immune-endocrine dysfunction with muscle T

mass and performance in cognitively impaired older adults
⁎
L. Taya, , B.P. Leungb, S. Weec, K.S. Tayb, N. Alic,d, M. Chanc,d, W.S. Limc,d
a
Department of General Medicine, Sengkang General Hospital, Singapore
b
Department of Rheumatology, Allergy and Immunology, Tan Tock Seng Hospital, Singapore
c
Institute of Geriatrics and Active Ageing, Tan Tock Seng Hospital, Singapore
d
Department of Geriatric Medicine, Tan Tock Seng Hospital, Singapore

A R T I C L E I N F O A B S T R A C T

Keywords: Background: With lean mass declining early in Alzheimer’s disease, muscle quality beyond quantity is relevant to
Sarcopenia physical performance. We sought to identify potentially modifiable factors for the differential loss of muscle
Cognitive impairment mass (pre-sarcopenia) and its performance (sarcopenia) in older adults with mild cognitive impairment (MCI)
Inflammation and mild-to-moderate Alzheimer’s disease (AD).
Endocrine
Methods: This is a cross-sectional study of 108 community-dwelling older adults with MCI and mild-to-moderate
AD. Participants were categorized as: (i) No sarcopenia (normal muscle mass), (ii) Pre-sarcopenia (low muscle
mass without weakness or slowness), (iii) Sarcopenia (low muscle mass AND weak grip strength and/or slow gait
speed) using Asian cut-offs. Muscle quality was defined as the ratio of grip and knee extension strength to
average arm and leg lean mass respectively. We measured cognitive, functional and physical (Short Physical
Performance Battery, SPPB) performance; physical activity level; nutritional status; and blood biomarkers of
inflammation and endocrine dysfunction.
Results: SPPB (p = 0.033) and activity level (p = 0.010) were highest in the pre-sarcopenic group. Pre-sarco-
penic group had highest arm muscle quality [10.6 (7.7–12.2) vs 13.9 (12.6–15.7) vs 11.3 (9.7–12.8),
p < 0.001], despite significantly lower appendicular lean mass than non-sarcopenic group. In multi-nomial
logistic regression reference to non-sarcopenic group, malnutrition independently increased risk for both pre-
sarcopenia (Relative risk = 7.53, 95% C.I 1.20–47.51, p = 0.032) and sarcopenia (Relative risk = 11.91, 95%
C.I 2.85–49.77, p = 0.001). A combined pro-inflammatory and endocrine deficient state significantly increased
the risk of sarcopenia (Relative risk = 5.17, 95% C.I 1.31–20.37, p = 0.019).
Conclusion: Malnutrition is a precursor for progressive loss of muscle mass, but a pro-inflammatory and endo-
crine deficient state may potentially aggravate decline in muscle quality to culminate in frank sarcopenia.

1. Introduction There is substantial overlap between the physical frailty phenotype

Body composition changes with progressive weight loss have been
observed in the earliest clinical stages of Alzheimer’s disease (AD) and
may precede onset of dementia, being driven predominantly by the loss
of lean mass (Burns, Johnson, Watts, Swerdlow, & Brooks, 2010;
Johnson, Wilkin, & Morris, 2006). Weight loss, along with declines in
muscle mass and performance, feature amongst the major components
of the physical frailty syndrome (Fried, Ferruci, Darer, Williamson, &
Anderson, 2004) which has been recognized as a distinct entity asso-
ciated with aggravated risk for adverse outcomes amongst cognitively
impaired older adults (Bilotta et al., 2012; Ni Mhaolain et al., 2012;
Oosterveld et al., 2014).
and sarcopenia, which is widely operationalized as decreased muscle
function accompanying the decline in muscle mass with advancing age,
and spans a continuum through pre-sarcopenia (low muscle mass),
sarcopenia (low muscle mass with low muscle strength or poor per-
formance), and severe sarcopenia (low muscle mass with low muscle
strength and poor performance) (Cruz-Jentoft et al., 2010). Indeed,
sarcopenia may be considered the biological substrate for the devel-
opment of physical frailty. There is, however, dissociation between the
loss of muscle mass and that of muscle strength, with higher rate of
decline in muscle strength and its greater impact on future disability
relative to muscle mass (Visser et al., 2005; von Haehling, Morley, &
Anker, 2010). In addition, muscle strength but not muscle mass

⁎
Corresponding author at: Department of General Medicine, Sengkang General Hospital, 378 Alexandra Road, 159964, Singapore.
E-mail address: laura.tay.b.g@singhealth.com.sg (L. Tay).

https://doi.org/10.1016/j.archger.2017.11.008
Received 12 July 2017; Received in revised form 8 October 2017; Accepted 14 November 2017
Available online 16 November 2017
0167-4943/ © 2017 Elsevier B.V. All rights reserved.
L. Tay et al.
independently predicted mortality in older adults (Newman et al.,
2006). This observed discrepancy between muscle mass and muscle
strength has shifted attention towards muscle quality as a more clini-
cally relevant determinant of physical performance in older adults
(Barbat-Artigas, Rolland, Zamboni, & Aubertin-Leheudre, 2012).
The consequences of muscle mass and strength declines extend be-
yond physical limitations, having been linked to cognitive impairment
and dementia (Nourhaehemi et al., 2002; Shin, Kim, Kim, Shin, & Yoon,
2002). Further, low muscle quality as represented by strength per unit
muscle mass has been associated with poorer cognitive performance
(Canon & Crimmins, 2011). The significant association between sar-
copenia and cognitive impairment raises the possibility of shared
common pathways (Chang, Hsu, Wu, Huang, & Han, 2016). Endocrine
systems involved in muscle anabolism such as insulin-like growth factor
1 (IGF-1) and dehydroepiandrosterone sulphate (DHEAS) have also
been implicated in age-related cognitive decline (Cruz-Jentoft et al.,
2014; Landi et al., 2012; Maggio et al., 2012; Watanabe et al., 2005),
while a chronic inflammatory state has been linked to both muscle
catabolism and AD (Holmes et al., 2009; Schaap et al., 2009). Beyond
their individual detrimental effects, the potential for additive effects of
inflammation and endocrine dysregulations has also been suggested
(Cappola et al., 2008).
The observed association of sarcopenia but not pre-sarcopenia with
dual impairments in cognitive and physical performance may be espe-
cially pertinent in cognitively impaired older adults (Tolea & Galvin,
2015), and suggests sarcopenia as a risk factor for accelerating disease
progression and disability. Compared with sarcopenic individuals who
are less likely to transition out, the pre-sarcopenic state with its greater
potential for reversibility offers an intervention target to avoid pro-
gression (Murphy et al., 2014). Little is known about risk factors that
differentiate pre-sarcopenia from non-sarcopenia and sarcopenia states,
although the inconsistent translation of gains in muscle mass to im-
provements in muscle strength raises the hypothesis for differential
pathways underlying muscle mass and function (Schroddder et al.,
2012). Thus, this study sought to identify potentially modifiable factors
associated with the differential loss of muscle mass (pre-sarcopenia)
and its performance (sarcopenia) in cognitively impaired older adults.
2. Methods
2.1. Study population
This is a cross-sectional analysis of community-dwelling older adults
with mild cognitive impairment (MCI) and mild-moderate Alzheimer’s
dementia (AD) attending a tertiary Memory Clinic, Tan Tock Seng
Hospital, Singapore. Informed written consent was obtained from the
patient or legally acceptable representative where appropriate, and the
study was approved by the Domain Specific Review Board (DSRB) of
the National Healthcare Group (NHG).
2.1.1. Diagnostic categories
MCI was defined as follows: (1) global Clinical Dementia Rating
(CDR) (Morris, 1993) score of 0.5; (2) presence of subjective memory
complaint which was corroborated by a reliable informant; (3) delayed
recall > 1 SD below the age and education-adjusted means of healthy
community-dwelling subjects derived from an earlier normative study
(Sahadevan, Lim, Tan, & Chan, 2002); (4) relatively normal general
cognitive function, defined as a score ≥21 for subjects with ≤6 years
education and ≥24 for those with > 6 years of education on the locally
validated modified Chinese version of Mini Mental State Examination
(CMMSE) (Sahadevan, Lim, Tan, & Chan, 2000), (5) largely intact ac-
tivities of daily living; and (6) no clinical dementia.
Mild-moderate AD subjects fulfilled National Institute of
Neurological and Communicative Disorders and Stroke and the
Alzheimer’s Disease and Related Disorders Association (NINCDS-
ADRDA) criteria for probable AD (McKhann et al., 1984), with global
21
Archives of Gerontology and Geriatrics 75 (2018) 20–27
CDR of 0.5, 1 or 2, corresponding to very mild, mild or moderate de-
mentia respectively. We excluded subjects with a diagnosis of possible
AD in view of the confounding co-morbid diagnoses and differing
clinical course in these individuals.
2.1.2. Eligibility criteria
Subjects were eligible if they were aged > 55 years, with a diag-
nosis of MCI or mild to moderate AD at baseline, community-dwelling,
and accompanied by a reliable informant.
We excluded subjects with presence of other central nervous con-
ditions (stroke disease, Parkinson’s disease, subdural hematoma,
normal pressure hydrocephalus, and brain tumor); presence of systemic
conditions that can contribute to cognitive impairment (hypothyr-
oidism, B12 deficiency, and hypercalcaemia); and presence of any ac-
tive neuropsychiatric conditions producing disability. Subjects living in
a sheltered or nursing home were also excluded.
The validity of the overall cognitive evaluation process and CDR
scoring has been previously established (Chong and Sahadevan, 2003;
Lim, Chin, Lam, Lim, & Sahadevan, 2005). Laboratory investigations to
exclude potentially reversible causes of dementia via blood tests and
neuroimaging were done. A multidisciplinary consensus meeting was
conducted to review all relevant results for accurate clinical pheno-
typing of the cognitive disorder (MCI or mild-moderate probable AD).
Patients meeting study eligibility criteria were then recruited.
2.2. Measures
2.2.1. Sarcopenia assessment and muscle quality
Grip strength was measured using the hydraulic hand dynamometer
(North Coast@ Hydraulic Hand Dynamometer), with two trials of grip
strength for each hand and all 4 trials averaged to yield strength. Knee
extensor muscle strength of each leg was measured twice using an
electronic dynamometer (BASELINE PUSHPULL Dynamometer), with
the participant seated at the edge of a chair and maintaining the trunk
in the upright position. The average of the 4 readings provided a
measure of knee extension strength. Gait speed was based on the time to
walk 3m.
Percentage body fat and lean mass measures were obtained via a
dual-energy X-ray absorptiometry system (Discovery™ APEX 13.3;
Hologic, Bedford, MA, USA). Appendicular skeletal mass was derived
from the summation of muscle mass measurements in the four limbs.
We adopted the European Working Group on Sarcopenia in Older
People (EWGSOP) consensus criteria (Cruz-Jentoft et al., 2010), but
employing Asian gender-specific cut-off values for muscle mass, grip
strength and gait speed (Chen et al., 2014), to delineate 3 groups: (i) No
sarcopenia (normal muscle mass), (ii) Pre-sarcopenia (low muscle mass
without impact on muscle strength or gait speed), (iii) Sarcopenia (low
muscle mass AND weak grip strength and/or slow gait speed).
A measure of muscle quality was derived for each individual from
the ratio of grip and knee extension strength to average arm and leg
lean mass respectively.
2.2.2. Cognitive assessment
We used the CDR (Morris, 1993), a structured clinician rating, to
determine dementia severity. The CDR is a global dementia rating scale
and ratings in each of the six domains can be summed for a CDR sum-of-
boxes (CDR-SB) score (range 0–18). The attending geriatrician, trained
in administration of the CDR, rated each patient’s CDR at baseline.
Cognitive performance was assessed using the locally-validated
modified Chinese version of Mini-Mental State Examination (CMMSE),
and MCI subjects also underwent a neuropsychological assessment
(Sahadevan et al., 2000).
2.2.3. Other clinical co-variates
Demographic data and co-morbid vascular risk factors – hyperten-
sion, hyperlipidemia, diabetes mellitus, atrial fibrillation, peripheral
L. Tay et al.
vascular disease, smoking history, ischemic heart disease – were cap-
tured at baseline. The presence of hypertension, hyperlipidaemia, dia-
betes mellitus, atrial fibrillation, peripheral vascular disease and
smoking was defined by self- or informant-report, documentation in
clinical notes or by the use of disease-specific medications. The pre-
sence of ischemic heart disease was defined as having a history of an-
gina, myocardial infarction, congestive heart failure or previous cor-
onary artery stenting or bypass surgery, verified against the patients’
medical records. Medical records were also reviewed for the presence of
chronic inflammatory disease and any active treatment with steroids or
immunosuppressant medication.
Standing height (m), body weight (kg) and waist circumference
(cm) were measured, and body mass index (BMI) was calculated using
the formula weight/height2 (kg/m2). With increasing recognition for
the limitation of BMI as an indicator of obesity as it includes lean mass
in its calculation without discriminating between muscle and fat dis-
tribution, A Body Shape Index (ABSI) was calculated for each individual
[ABSI = Waist circumference/(BMI2/3Height1/2)], which allows for
better representation of central body volume (Krakauer & Krakauer,
2012).
Functional ability was evaluated using Barthel’s basic activities of
daily living (ADL) index (Mahoney & Barthel, 1965) and Lawton and
Brody’s instrumental ADL (iADL) index (Barbeger-Gateau et al., 1992).
Physical performance was measured using the Short Physical Perfor-
mance Battery (SPPB) (Guralnik et al., 1994), which assessed balance in
the side-by-side, semi-tandem and tandem positions; gait speed; and
lower limb strength and power on the single and repeated chair stands.
Physical activity level was captured using the Frenchay activity scale
(Wade, Legh-Smith, & Langton Hewer, 1985). Nutrition was system-
atically assessed using the locally validated mini nutritional assessment
(MNA) questionnaire (Chan et al., 2010).
We reviewed each subject’s neuroimaging scan – brain computed
tomography (CT) scan or magnetic resonance imaging (MRI). White
matter lesion (WML) severity was graded using the Age-Related White
Matter Changes (ARWMC) scale by a blinded rater (Wahlund et al.,
2001). Medial temporal atrophy (MTA) score reflecting neurodegen-
eration was scored on T1-weighted coronal slices parallel to the
brainstem axis and perpendicular to the hippocampal axis, by a con-
sensus method where the scores range from 0 (no atrophy) to 4 (severe
atrophy) (Wahlund, Julin, Johansson, & Scheltens, 2000).
Total 25-hydroxy vitamin D level was measured at baseline, and
APOE genotyping into APOEε2,3,4 isoforms was performed via re-
striction enzyme analysis using applied biosystems platform- ABI Prism
310 Genetic Analyser.
2.2.4. Blood biomarkers
All subjects underwent baseline blood biomarker measurements.
Blood was drawn following an 8-h fast and the aliquoted serum was
frozen and stored at −80 °C until the tests were performed.
Inflammatory status was assessed by serum levels of soluble tumour
necrosis factor-α receptor-1 (TNF-R1, R&D Systems, Minneapolis, MN,
USA), interleukin-6 (high sensitive IL-6, eBioscience, San Diego, CA,
USA), and the acute phase reactant C-reactive protein (CRP,
eBioscience) via ELISA. The endocrine markers IGF-1 and DHEAS were
quantified using commercial ELISA assays (BioVendor, Brno, Czech
Republic and Abcam, Cambridge, UK respectively). All biomarkers were
measured in duplicates according to manufacturers’ recommendations,
and the average value was reported for all assays. Detection limits were
as follows: DHEAS, 0.2 μmol/L; IGF-1, 5 ng/ml; IL-6, 0.1 pg/ml; TNF-
R1, 20 pg/ml.
To examine the impact of an elevated inflammatory state or endo-
crine deficiency, we adopted quartile cut-offs from a local cohort of
cognitively well and independent older adults, with the highest quartile
for IL-6 and TNF-R1 considered pro-inflammatory, and the lowest
quartile for IGF-1 being deficient. The lowest quartile of DHEAS in the
current cohort was used to define DHEAS deficiency. Each subject was
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Archives of Gerontology and Geriatrics 75 (2018) 20–27
subsequently categorized as (i) neither pro-inflammatory nor endocrine
deficient, (ii) pro-inflammatory (IL-6 or TNF-R1, or both, being in
highest quartile) but not endocrine deficient, (iii) endocrine deficient
(IGF-1 or DHEAS, or both, being in lowest quartile) but not pro-in-
flammatory and (iv) both pro-inflammatory and endocrine deficient.
2.3. Statistical analyses
Descriptive data are presented as means (+SD) or median (inter-
quartile range, IQR) for quantitative variables and as absolute and re-
lative frequencies for categorical variables. We performed univariate
analyses comparing no sarcopenia, pre-sarcopenia and sarcopenia
groups in baseline demographics, clinical measures of cognitive, func-
tional and physical performance, vascular co-morbidities and blood
biomarker measurements using One-way ANOVA and Kruskal-Wallis
tests for parametric and non-parametric continuous variables respec-
tively, and Chi-square and Fisher’s exact tests for categorical variables.
Multinomial logistic regression, with the referent group being non-
sarcopenia, was performed to identify factors independently associated
with the differential loss of skeletal muscle mass and function. The
model included potentially modifiable factors that were observed to be
significant on univariate analysis, adjusted a priori for age, gender and
severity of cognitive impairment.
Statistical analyses were performed using STATA version 14 (Stata
Corp., College Station, TX). All statistical tests were two-tailed, with p
value < 0.05 considered statistically significant
3. Results
3.1. Clinical characteristics (Table 1)
We recruited 129 subjects between December 2012 and July 2015.
108 subjects had complete baseline clinical assessments, blood bio-
marker measurements and DXA imaging, and were included for ana-
lysis, with the mean age being 76.7 + 6.5 years, female predominance
(64.8%) and majority of Chinese ethnicity (92.6%). There was no dif-
ference in age, gender and severity of cognitive impairment between
participants with DXA imaging and those who were excluded due to
unavailability of DXA results.
Forty-one (38%) subjects were non-sarcopenic, 14 (13%) were pre-
sarcopenic and 53 (49%) were sarcopenic at baseline. Sarcopenic sub-
jects were significantly older (76.5 + 5.5 vs 72.4 + 7.6 vs 78.3 + 6.5,
p = 0.008), while the pre-sarcopenic group had significantly more
male subjects. While a significant difference in CMMSE scores was
observed across groups, being highest in pre-sarcopenia, the 3 groups
were similar in baseline severity of cognitive impairment as assessed
using diagnostic categories (MCI, mild AD or moderate AD) and CDR
(global and sum-of-boxes) scores. All vascular co-morbidities examined
were similarly distributed across groups, and there was no difference in
severity of white matter lesions on neuroimaging scans between groups.
Only 95 subjects had the appropriate neuroimaging coronal slices for
evaluation of hippocampal atrophy, with no observed difference in
MTA scores between groups. Overall prevalence of chronic in-
flammatory disease was low in our cohort (1.9%).
Physical performance and activity level were significantly different
across groups, with pre-sarcopenic group having highest SPPB and FAI
scores. No subject was overtly malnourished based on MNA total
score < 17, and the non-sarcopenic group was least likely to be at-risk
of malnutrition (MNA total score 17–23.5: 7.3% vs 42.9% vs 47.2%,
p < 0.001). There was no difference in serum Vitamin D levels and
ApoE4 status between groups.
3.2. Body composition and muscle quality (Table 2)
ABSI was similar across groups, despite observed significant dif-
ference in BMI, being highest in non-sarcopenic group. Not
L. Tay et al. Archives of Gerontology and Geriatrics 75 (2018) 20–27

Table 1 unexpectedly, appendicular lean mass was highest in the non-sarco-

Baseline Clinical Characteristics. penic group. We observed lowest average fat mass in both upper and
lower extremities in the pre-sarcopenic group, who also had sig-
Sarcopenia Status p value
nificantly lowest percentage body fat. Muscle quality as a ratio of grip
No sarcopenia Pre-sarcopenia Sarcopenia strength to arm lean mass was highest in the pre-sarcopenic group [10.6
(n = 41) (n = 14) (n = 53) (7.7–12.2) vs 13.9 (12.6–15.7) vs 11.3 (9.7–12.8), p < 0.001].
With recognized differences in body composition between genders,
Demographics
Age 76.2 (5.5) 72.4 (7.6) 78.3 (6.5)* 0.008 we performed subgroup analysis separately for men and women. ABSI
Gender (male, %) 11 (26.8%) 9 (64.3%) 18 (34%) 0.039 was similar across groups regardless of gender. While percentage body
Ethnicity 37 (90.2%) 13 (92.9%) 50 (94.3%) 0.433 fat was similarly distributed across groups in women, pre-sarcopenic
(Chinese, %) men exhibited a trend for having lowest percentage body fat. Muscle
Diagnostic Categories (%) quality in the upper limbs differed significantly and was highest in the
Mild cognitive 8 (19.5%) 4 (28.6%) 6 (11.3%) pre-sarcopenic group in both genders [men: 11.9 (10.8–13.5) vs 13.9
impairment
(12.6–14.8) vs 11.5 (9.2–12.5), p = 0.008; women: 9.2 (7.4–12.2) vs
Mild AD 28 (68.3%) 9 (64.3%) 37 (69.8%) 0.471
Moderate AD 5 (12.2%) 1 (7.1%) 10 (18.9%) 13.8 (13.0–6.2) vs 11.3 (9.8–12.8), p = 0.002].
Due to the observed significantly poorer physical performance on
Co-morbidities
Hypertension 28 (68.3%) 10 (71.4%) 34 (64.2%) 0.882 SPPB in non-sarcopenic compared with pre-sarcopenic group despite
Diabetes mellitus 10 (24.4%) 3 (21.4%) 20 (37.7%) 0.280 normal muscle mass, we performed sub-group analysis for the non-
Hyperlipidaemia 30 (73.2%) 12 (85.7%) 32 (60.4%) 0.158 sarcopenic group, comparing participants with impaired muscle per-
Ischemic heart 6 (14.6%) 1 (7.1%) 13 (24.5%) 0.269 formance (weak grip strength and/or slow gait speed) versus their
disease
counterparts with preserved muscle performance. 29 (70.1%) non-sar-
Atrial fibrillation 2 (4.9%) 1 (7.1%) 1 (1.9%) 0.462
Smoking 5 (13.9%) 3 (21.4%) 9 (17%) 0.735 copenic participants had impaired muscle performance, with sig-
Stroke/ transient 2 (4.9%) 0 1 (1.9%) 0.723 nificantly lower SPPB [10 (9.5–11) vs 7 (5–9), p = 0.002] and FAI [26
ischemic attack (21–34.5) vs 18 (14–21), p = 0.002] scores, although appendicular
Chronic 1(2.4%) 0 1 (1.9%) 1.00
lean mass was similar between groups (6.8 + 0.34 vs 6.3 + 0.16,
inflammatory
disease
p = 0.096). While there was no difference in age, non-sarcopenic par-
ticipants with impaired muscle performance were more likely to be
Major depressive 2 (4.9%) 0 1 (1.9%) 0.723
disorder
female (p = 0.007) and had more severe cognitive impairment [CRD
sum-of-boxes: 5 (2–6) vs 2.25 (1.25–5), p = 0.039] (Supplementary
Cognitive Performance
Table).
CDR global 0.213
0.5 16 (39%) 5 (35.7%) 10 (18.9%)
1 20 (48.8%) 8 (57.1%) 32 (60.4%) 3.3. Inflammatory-endocrine biomarkers (Table 3)
2 5 (12.2%) 1 (7.1%) 11 (20.8%)
CDR sum-of- 4.4 (3.0) 4.1 (2.5) 5.4 (2.9) 0.140
The pro-inflammatory cytokines IL-6 and TNF-R1 did not differ-
boxes (mean,
SD)
entiate between non-, pre- and sarcopenic groups, in both absolute
CMMSE (mean, 18.5 (5.5) 21.5 (3.4) 17.4 (5.3)* 0.036 serum concentrations and when upper quartile cut-offs were employed.
SD) Serum concentrations of the acute phase protein CRP were similar
Neuroimaging across groups.
ARWMC score 6.17 (4.58) 4.64 (3.10) 5.16 (4.52) 0.410 In the endocrine axes, serum IGF-1 concentration was significantly
MTA score 1.43 (1.01) 1.29 (0.91) 1.47 (1.05) 0.828 different across groups, being lowest in the sarcopenic group and
(n = 95)
highest in pre-sarcopenic. Adopting the lowest quartile of serum IGF-1
Neuropsychiatric Symptoms concentration to define an IGF-1 deficient state, sarcopenic subjects
NPI severity 4 (1–6) 2 (0–2) 3 (1–5) 0.069
were most likely to be IGF-1 deficient, while pre-sarcopenic subjects
(median, IQR)
were least likely to exhibit IGF-1 deficiency (29.3% vs 14.3% vs 56.6%,
Functional Performance p = 0.003). There was no significant difference in serum DHEAS con-
MBI (median, 100 (95–100) 100 (100–100) 100 (95–100) 0.269
IQR)
centration across groups, although a trend for higher prevalence of a
iADL (median, 15 (11–19) 17.5 (15–20) 14 (10–18) 0.088 DHEAS-deficient state was observed with sarcopenia.
IQR) When pro-inflammatory and endocrine-deficient states were ex-
Physical Performance amined in tandem, sarcopenic group was least likely to be in the “ideal”
SPPB (median, 8 (7–10) 10 (10–11) 9 (7–10) 0.033 state of being neither pro-inflammatory nor endocrine deficient, and
IQR) had the highest proportion of subjects being in the combined pro-in-
FAI (mean, SD) 21 (8.6) 26.9 (8.0) 19.4 (7.3)* 0.010 flammatory and endocrine-deficient state (17.1% vs 14.3% vs 41.5%,
Nutritional Status p = 0.016).
MNA-at risk of 3 (7.3%) 6 (42.9%) 25 (47.2%) < 0.001
malnutrition
3.4. Factors independently associated with pre-sarcopenia and sarcopenia
Vitamin D (mean, 20.7 (9.1) 24.8 (8.2) 20.3 (11.5) 0.341
SD) (Table 4)
ApoE status
ApoE4 positive 17 (41.5%) 8 (57.1%) 14 (27.5%) 0.091 We performed multi-nomial logistic regression with non-sarcopenia
as the reference group, and included in the model nutritional status and
AD: Alzheimer’s disease; ARWMC: age-related white matter changes (range 0–30); CDR: inflammatory-endocrine state as the independent potentially modifi-
Clinical Dementia Rating; CMMSE: Chinese Mini-Mental State Examination (range able variables, adjusted a priori for age, gender, and CDR sum-of-boxes
0–28);) FAI: Frenchay Activity Index (range: 0–45); iADL: Lawton and Brody’s instru-
score. We excluded percentage body fat owing to collinearity with
mental Activities of Daily Living (range 0–23); MBI: Modified Barthel Index (range
nutritional status. Malnutrition was associated with significantly in-
0–100); MNA: Mini Nutrition Assessment; SPPB: Short Physical Performance Battery
(range 0–12). creased risk for both pre-sarcopenia (Relative risk ratio = 7.53, 95% C.I
* p < 0.05 between sarcopenia and pre-sarcopenia. 1.20–47.51, p = 0.032) and sarcopenia (Relative risk ratio = 11.91,
95% C.I 2.85–49.77, p = 0.001). Inflammatory-endocrine state was not

23
L. Tay et al. Archives of Gerontology and Geriatrics 75 (2018) 20–27

Table 2
Body Composition and Muscle Quality.

Sarcopenia Status p value

No sarcopenia Pre-sarcopenia Sarcopenia

(n = 41) (n = 14) (n = 53)

Body Composition
BMI (mean, SD) 25.4 (3.3) 21.2 (2.3) 21.7 (3.2) < 0.001
ABSI 0.083 (0.005) 0.085 (0.006) 0.086 (0.006) 0.155

DXA Imaging
Appendicular Lean Mass (kg/m2) (mean, SD) 6.45 (0.86) 5.83 (0.85)** 5.32 (0.78)# < 0.001
Average fat mass arm (g) (mean, SD) 1240.2 (451.5) 913.0 (308.4)** 1002.1 (322.5)# 0.003
Average fat mass leg (g) (mean, SD) 3391.8 (1050.5) 2649.0 (884.4)** 2661.8 (740.1)# < 0.001
% body fat 38.5 (9.3) 30.8 (8.5)** 36.3 (6.6) 0.010

Muscle Quality
Arm muscle quality (kg/kg) (median, IQR) 10.6 (7.7–12.2) 13.9 (12.6–15.7) 11.3 (9.7–12.8) < 0.001
Leg muscle quality (kg/kg) (mean, SD) 5.8 (1.8) 5.8 (1.5) 6.0 (1.8) 0.901

Men (n = 38) Women (n = 70)

No sarcopenia Pre-sarcopenia Sarcopenia No sarcopenia Pre-sarcopenia Sarcopenia

(n = 11) (n = 9) (n = 18) (n = 30) (n = 5) (n = 35)

DXA Imaging
Appendicular Lean Mass (kg/m2) (mean, SD) 7.56 (0.71) 6.35 (0.54)** 6.16 (0.66)*,# 6.05 (0.46) 4.9 (0.27)** 4.89 (0.40)*,#
% body fat 36.3 (14.9) 26.3 (6.6) 30.9 (6.3) 39.3 (6.4) 39.0 (4.2) 39.2(4.7)

Muscle Quality
Arm muscle quality (kg/kg) (median, IQR) 11.9 (10.8–13.5) 13.9 (12.6–14.8) 11.5 (9.2–12.5)* 9.2 (7.4–12.2) 13.8 (13.0–6.2) 11.3 (9.8–12.8)*
Leg muscle quality (kg/kg) (mean, SD) 6.2 (1.1) 5.4 (1.1) 5.5 (1.7) 5.7 (2.0) 6.4 (1.9) 6.2 (1.8)

ABSI: A New Body Shape Index; BMI: Body Mass Index.

* p < 0.05 across groups.
** p < 0.005 between pre-sarcopenia and no sarcopenia.
#
p < 0.05 between sarcopenia and no sarcopenia.

associated with pre-sarcopenia, but the combined state of being pro-
inflammatory and endocrine deficient significantly increased the risk of
sarcopenia (Relative risk ratio = 5.17, 95% C.I 1.31–20.37,
p = 0.019).
While women were significantly less likely to be pre-sarcopenic,
sarcopenia risk was independent of gender. Severity of cognitive im-
pairment was not associated with pre-sarcopenia or sarcopenia.
4. Discussion
Our study supports the clinical relevance of muscle quality beyond
muscle mass as a determinant of functional performance in cognitively
impaired older adults, evident by the pre-sarcopenic group being the
most physically active and exhibiting highest physical performance
despite their low muscle mass. While malnutrition is a precursor for
progressive loss of muscle mass, being the common risk factor for pre-
sarcopenia and sarcopenia, a combined pro-inflammatory and endo-
crine deficient state aggravates decline in muscle performance culmi-
nating in frank sarcopenia.
Previous research had shown that changes in muscle mass explained
only 6–8% of the variability in muscle strength among older adults
(Goodpaster et al., 2006). Indeed, the dissociation between muscle mass
and physical performance in the pre-sarcopenic group, such that muscle
quality as reflected by grip strength per unit arm lean mass and SPPB
scores are higher relative to the non-sarcopenic group, suggests that the
efficiency of muscle tissue has greater impact on functional con-
sequences compared with an isolated decline in muscle mass. This is
further reinforced by findings within the non-sarcopenic group whereby
70% of subjects had impairments in performance on grip strength or
gait speed despite normal muscle mass, with significantly poorer
muscle quality compared with their counterparts with preserved muscle
performance measures.
Consistent with widely reported literature, malnutrition was an
independent risk factor for decline in muscle mass, with incremental
risk for pre-sarcopenia and sarcopenia. However, in the pre-sarcopenic
group, the poorer nutritional status was not sufficient to yield a com-
promise in muscle quality and, consequently, physical performance.
While 2 out of 3 malnourished older adults were physically frail, only
10% of physically frail seniors were noted to be malnourished (Verlaan
et al., 2017). Our findings thus further suggest that nutrition may be a
key substrate for muscle mass, but other mechanisms may be driving
the qualitative decline beyond quantitative muscle loss, to culminate in
functional deficits clinically manifest as sarcopenia and its sequelae of
physical frailty. This will be of clinical significance in light of the recent
systematic review in which nutritional intervention in isolation failed to
yield improvement in muscle strength among older people with re-
duced functional ability (Beck, Dent, & Baldwin, 2016).
As further support of our hypothesized differential mechanisms for
the quantitative and qualitative declines in skeletal muscle, in-
flammatory-endocrine dysregulation conferred a five-fold higher risk
for sarcopenia, despite not being associated with pre-sarcopenia. The
differential association suggests that against a background of declining
muscle mass, a heightened state of inflammation in tandem with en-
docrine deficiency impairs muscle performance. Our findings also
parallel previously reported differences in related factors for muscle
mass and function, as declines in growth hormone and IGF-1 have been
linked to loss of muscle mass but not muscle power (Morley, 2016),
which corroborate the observed lack of a significant impact of an iso-
lated endocrine deficient state on the risk of sarcopenia. The detri-
mental effect of a combined pro-inflammatory and endocrine deficient
state, over the isolated presence of either inflammation or endocrine
deficiency, is concordant with previously reported synergistic effects of
IGF-1 and IL-6 on progressive disability (Cappola et al., 2008) as well as
both in-vivo and in-vitro observed interactions between anabolic hor-
mones and pro-inflammatory cytokines (Andreassen et al., 2010;
Lelbach, Scharf, & Ramadori, 2001). The current findings seemingly

24
L. Tay et al. Archives of Gerontology and Geriatrics 75 (2018) 20–27

Table 3 when occurring in isolation rather than being in tandem with an en-
Inflammatory and Endocrine Biomarkers. docrine-deficient state (Tay, Lim, Chan, Ye, & Chong, 2016). However,
the observed physical performance limitations despite normal muscle
Sarcopenia Status p value
mass in approximately one-quarter of our cohort suggest that there may
No Pre- Sarcopenia be non-muscle pathways to physical frailty. Indeed, slowness and
sarcopenia sarcopenia weakness – the core characteristics of sarcopenia and physical frailty-
(n = 41) (n = 14) (n = 53) are commonly associated with neurological conditions. This is also re-
Pro-inflammatory Cytokines inforced by the observation of Huang et al., who noted that slowness
IL-6 (pg/ml, median, 0.17 0.28 0.2 0.521 and weakness with non-muscle etiology were strongly associated with
IQR) (0.1–0.47) (0.06–0.57) (0.1–0.69) cognitive impairment (Huang et al., 2016). Dysfunctions in the per-
Elevated IL-6 (%) 2 (4.9%) 0 8 (15.1%) 0.150 ipheral and central nervous system have been implicated in muscle
TNF-R1 (pg/ml, 4883.5 4892.6 5256.5 0.504
quality (Moore et al., 2014), and may account for the observed higher
mean, SD) (1648.0) (1149.6) (1735.7)
Elevated TNF-R1 16 (39%) 7 (50%) 27 (50.9%) 0.494 cognitive performance scores in the pre-sarcopenic group compared
(%) with both non-sarcopenic and sarcopenic groups. In addition, we ob-
CRP (mg/L, median, 0.14 0.19 0.10 0.458 served worse cognitive performance within the non-sarcopenic group
IQR) (0.06–0.33) (0.11–0.45) (0.05–0.36)
with impaired muscle performance. Yet, the overall lack of an asso-
Endocrine ciation between the stage of severity of cognitive impairment and sar-
IGF-1 (ng/ml, mean, 139.2 (80.0) 155.0 (89.7) 97.3 (64.9)*,# 0.006 copenia status is similar to the findings of the EPIDOS cohort, which
SD)
IGF-1 deficient (%) 12 (29.3%) 2 (14.3%) 30 (56.6%) 0.003
found no link between different operative definitions of sarcopenia and
DHEAS (μmol/L, 1.95 1.49 1.50 0.135 cognitive impairment, despite independent and significant associations
median, IQR) (1.3–2.96) (1.04–3.30) (0.81–2.12) between grip strength and gait speed with cognition (Abellan van Khan
DHEAS deficient (%) 7 (17.1%) 2 (14.3%) 18 (34.0%) 0.119 et al., 2013). Together, these observations suggest that functional per-
Inflammatory-Endocrine (%) formance measures rather than muscle mass parameters are associated
Non-inflammatory- 16 (39%) 5 (35.7%) 8 (15.1%) with cognition. Further investigations detailing the mechanisms that
Non-endocrine
link cognitive impairment, sarcopenia and physical frailty may be an-
deficient
Pro-inflammatory 10 (24.4%) 5 (35.7%) 8 (15.1%) 0.016
ticipated to allow a more targeted interventional approach.
Endocrine deficient 8 (19.5%) 2 (14.3%) 15 (28.3%) Beyond neurological factors, changes in muscle architecture in re-
Pro-inflammatory- 7 (17.1%) 2 (14.3%) 22 (41.5%) lation to anthropometrics have been implicated in functional impair-
Endocrine ment of muscle (Goodpaster et al., 2001; Vilaca et al., 2014). In parti-
deficient
cular, intermuscular adipose tissue (IMAT) is an ectopic depot of
DHEAS: dehydroepiandrosterone sulphate; IGF-1: insulin-like growth factor-1; TNF-R1: adipose tissue underneath the fascia and within muscle that has been
tumour necrosis factor-alpha receptor-1. implicated in muscle quality and function in older adults, and may
* p < 0.05 between sarcopenia and pre-sarcopenia. reflect metabolic profile (Beavers et al., 2013). Of significance within
#
p < 0.05 between sarcopenia and no sarcopenia. our study is the lower fat mass in the pre-sarcopenic group, with cor-
respondingly lowest percentage body fat, that highlights the potential
Table 4 for a detrimental effect of adiposity on muscle quality. The relationship
Multinomial Logistic Regression for Factors Associated with Sarcopenia Status. between adiposity and muscle quality is further clarified in a recent
study reporting poorer muscle quality and physical performance in
Relative Risk 95% Confidence p value
Ratio Interval obese women despite a greater quantity of fat free and lean mass
(Vilaca et al., 2014). In parallel with earlier evidence that gender dif-
Pre-sarcopenia ferences may exist in muscle quality measures (Frontera, Hughes, Lutz,
Age 0.88 0.77–1.01 0.070
& Evans, 1991), men were more likely to exhibit preserved physical
Gender (female) 0.13 0.02–0.67 0.015
CDR sum-of-boxes 1.02 0.76–1.35 0.917 performance despite loss of muscle mass (pre-sarcopenia). We have
previously reported differential pathophysiological mechanisms for
MNA-at risk of malnutrition 7.53 1.20–47.51 0.032
sarcopenia in community-dwelling cognitively intact older adults (Tay
Inflammatory-Endocrine et al., 2015), although the sample size of the current study limits further
Proinflammatory 1.89 0.27–13.12 0.520
Endocrine deficient 1.06 0.12–9.16 0.960
sub-group analysis by gender. Earlier studies demonstrating that im-
Proinflammatory-Endocrine 1.59 0.17–14.49 0.681 provement in muscle function need not be accompanied by gains in
deficient muscle mass suggest that muscle weakness culminates from impaired
Sarcopenia muscle quality rather than quantity. Such qualitative changes have also
Age 1.04 0.95–1.14 0.359 been linked to loss of motor units, muscle fibrosis, degeneration of
Gender (female) 0.83 0.26–2.64 0.751 neuromuscular junction, reduced muscle aerobic capacity and reduced
CDR sum-of-boxes 1.08 0.90–1.29 0.432
excitation-contraction coupling (McGregor et al., 2014).
MNA-at risk of malnutrition 11.91 2.85–49.77 0.001 The prevalence of sarcopenia (49%) in our current cognitively im-
Inflammatory-Endocrine paired cohort of older adults is almost twice as high as the previously
Proinflammatory 1.31 0.29–5.37 0.727 reported prevalence of sarcopenia in our local cohort of cognitively
Endocrine deficient 2.12 0.53–8.50 0.289 intact community-dwelling older adults, applying similar diagnostic
Proinflammatory-Endocrine 5.17 1.31–20.37 0.019
algorithms and cut-offs for diagnosis of sarcopenia (Tay et al., 2015).
deficient
The higher prevalence is consistent with the findings of a recent sys-
R2 = 0.234. tematic review, which found a positive association between sarcopenia
Reference state: Non-sarcopenia. and impaired cognition, suggesting that the co-occurrence of both
CDR: Clinical Dementia Rating; MNA: Mini Nutritional Assessment. conditions is common (Chang et al., 2016). Further, the prevalence of
sarcopenia has also been shown to vary across populations and settings
contradict our previous study in which the detrimental effect of a pro- (Cruz-Jentoft et al., 2014).
inflammatory state on physical frailty – typically considered a sequelae We acknowledge several limitations in our study, including the re-
of sarcopenia – in cognitively impaired older adults was significant only latively small sample size, in particular the pre-sarcopenic group, with

25
L. Tay et al.
consequent possible type 2 error. The cross-sectional analysis limits
inference on temporal relationships between sarcopenia and its risk
factors, and the potential for alterations in the measured blood bio-
markers being consequent to changes in body composition cannot be
confidently dismissed. Additionally, the assessment of muscle strength
could have been influenced by cognitive function, given the observed
higher cognitive performance scores in the pre-sarcopenic group and
more severe cognitive impairment in non-sarcopenic subjects with
physical performance limitations. However, the recruited subjects had a
generally milder severity of cognitive impairment, having excluded
subjects with advanced dementia, and they were able to perform all
clinical assessments as instructed. Our careful phenotyping and exclu-
sion of participants with other central nervous conditions such as stroke
disease reduces the likelihood for physical performance being influ-
enced by neurological conditions other than neurodenegeration.
Nonetheless, the study’s inclusion/exclusion criteria limits general-
izability beyond the earlier stages of dementia, and its restriction to a
Memory Clinic population potentially limits interpretation in less spe-
cialized settings such as primary care.
In conclusion, the present study corroborates existing literature for
the dissociations between muscle mass, strength and physical perfor-
mance, but being specific to cognitively impaired older adults. The
ability to maintain physical performance despite the loss of muscle
mass reiterates the important concept of muscle quality relevant to
delaying disability in cognitively impaired older adults. While opti-
mizing nutritional status will undoubtedly remain important to prevent
progressive loss of muscle mass, more targeted interventions that si-
multaneously address immune and endocrine dysfunctions will be ne-
cessary to ensure maintenance of functional independence through
preserving muscle quality.
Conflicts of interest
All the authors have no conflict of interest or financial disclosure of
note.
Funding support
This study was funded by NHG Clinician Scientist Career
SchemeCSCS/12002 and NHG CSCS/13001.
Acknowledgements
We thank Prof Tan Eng King and Ms Ebonne Ng for the ApoE gen-
otyping. We also extend our thanks to our patients and their caregivers
who have graciously consented to participation in the study.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the
online version, at https://doi.org/10.1016/j.archger.2017.11.008.
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