Clinical correlates of sarcopenia and falls in Parkinson's disease.

BACKGROUND: Sarcopenia is a complex and multifactorial geriatric condition seen in several chronic degenerative diseases. This study aimed to screen for sarcopenia and fall risk in a sample of Parkinson's disease (PD) patients and to investigate demographic and clinical factors associated.
METHODS: This is a cross-sectional study. We evaluated 218 PD patients at the Movement Disorders Clinic in Fortaleza, Brazil, and collected clinical data including experiencing falls in the six months prior to their medical visit. Probable sarcopenia diagnosis was confirmed by using a sarcopenia screening tool (SARC-F questionnaire) and the presence of low muscle strength.
RESULTS: One hundred and twenty-one patients (55.5%) were screened positive for sarcopenia using the SARC-F and 103 (47.4%) met the criteria for probable sarcopenia. Disease duration, modified Hoehn and Yahr stage, Schwab and England Activities of Daily Living Scale score, levodopa equivalent dose, probable sarcopenia and positive SARC-F screening were all associated with experiencing falls. Disease duration, lower quality of life and female gender were independently associated with sarcopenia. Experiencing falls was significantly more frequent among patients screened positive in the SARC-F compared to those screened negative.
CONCLUSIONS: Sarcopenia and PD share common pathways and may affect each other's prognosis and patients' quality of life. Since sarcopenia is associated with lower quality of life and increased risk of falls, active case finding, diagnosis and proper management of sarcopenia in PD patients is essential.

Introduction

Sarcopenia is a complex and multifactorial geriatric condition seen in several chronic degenerative diseases. It stems from abnormally reduced muscle mass quality and quantity and is associated to several negative outcomes such as falls, disability, poor quality of life, institutionalization, hospitalization, and death [1]. The prevalence of sarcopenia has increased and it has become a serious global public health concern [2]. Patients with Parkinson’s disease (PD) show higher prevalence of sarcopenia and higher frequency of falls compared to non-PD patients [3,4]. Despite its importance, few studies have assessed the prevalence and characteristics of sarcopenia in this population [5-9].

Falls are a serious concern in PD with an annual incidence of 60% among PD patients. The risk of falls is greater in this population compared to healthy individuals and those with other neurological diseases with high risk of falls such polyneuropathy, spinal disorders and multiple sclerosis [10]. It is very important to early detect sarcopenia and fall risk in PD patients because they can benefit from simple interventions such as high-protein diet and resistance exercise training [5].

To the best of our knowledge, there are no large studies on the prevalence of sarcopenia and falls and associated risk factors in PD patients in Brazil. The aim of this study was to screen for sarcopenia and prevalence of falls in a sample of PD patients using a well-established screening tool for sarcopenia (SARC-F) [11]. In addition, we investigated demographic and clinical factors associated with sarcopenia and fall risk and their impact on the quality of life in PD patients.

Materials and methods

Study subjects

The study sample comprised consecutive patients with PD attending the Movement Disorders Clinic at Hospital Universitário Walter Cantídio in Fortaleza, Brazil, from January 2018 to August 31, 2019. The participants were regularly followed up at the clinic every 4–6 months. The diagnosis of PD was confirmed according to the Movement Disorders Society and the United Kingdom Parkinson’s Disease Brain Bank criteria. Patients who did not meet the clinical diagnostic criteria for idiopathic PD were excluded. The study was approved by the Research Ethics Committee of Hospital Universitário Walter Cantídio and all participants gave their written informed consent (register number 91075318.1.0000.5045). All patients were interviewed and evaluated by the study investigators.

Clinical evaluation

We used a structured interview to collect sociodemographic and clinical information including gender, age, age at onset of PD and disease duration. We evaluated past history of hypertension, diabetes, depression (according to the Diagnostic and Statistical Manual of Mental Disorders, DSM-V) [12], dementia (according to DSM-V) [12] and osteoporosis (according to National Osteoporosis Foundation recommendations) [13]. Clinical information from the patients was cross-checked with data from relatives, caregivers, and clinical records for accuracy. We also collected information on antiparkinsonian drug treatments used including L-dopa (L-dopa/carbidopa, L-dopa/benserazide and controlled-release L-dopa formulations), COMT inhibitors (entacapone), MAO-B inhibitors (rasagiline), amantadine and dopamine agonists (pramipexole). We defined the levodopa equivalent dose (LED) of an antiparkinsonian drug as the dose that produces the same level of symptomatic control as 100 mg of immediate release L-dopa according to Tomlinson et al. systematic review [14]. We recorded the number of medications used by each patient and defined as polypharmacy if they were on 5 or more. We used the Schwab and England Activities of Daily Living (SE ADL) Scale [15] to evaluate ADL, the modified Hoehn and Yahr (HY) staging [16] to assess PD severity and the Parkinson’s Disease Questionnaire (PDQ-39) [17] to assess quality of life. Depressive symptoms were assessed using the 15-item Geriatric Depression Scale (GDS-15) [18].

Assessment of sarcopenia

The SARC-F was administered to all patients [11]. The European Working Group on Sarcopenia in Older People (EWGSOP) [19] recommends the use of the SARC-F as a way to elicit self-reports from patients on signs that are characteristic of sarcopenia and to introduce assessment and treatment of sarcopenia into clinical practice. The SARC-F is an inexpensive and convenient tool for screening sarcopenia risk that can be readily used in community healthcare units and other clinical settings. It has 5 items to assess the patient’s perception of his or her limitations in strength, walking ability, rise from a chair, climb stairs and falls.

Functional lower extremity strength was measured with the Five Times Sit-to-Stand (FTSTS) test. Participants were asked to stand up from a sitting position and sit down 5 times as quickly as possible without pushing off. Those who could not rise with their arms folded across the chest were excluded from this test. Trained staff recorded the time a participant took to consecutively stand up 5 times from a seated position on a 45-cm-tall chair with the arms folded across the chest. The time from the command “Go” until the participant reached the chair on the fifth repetition was recorded once in seconds with a stopwatch. The cut-off point for low strength by FTSTS test is 15 seconds [20].

Hand grip strength was assessed using a dynamometer (JAMAR) for three repetitions in each hand. The average of three measures was recorded. The cut-off points for grip strength is 27 kg for men and 16 kg for women [21]. The highest value recorded in either hand was included in the statistical analysis.

The diagnosis of sarcopenia was based on EWGSOP criteria [19]. The diagnosis of probable sarcopenia was confirmed by screening positive in the SARC-F (score ≥4) and the presence of low muscle strength measured by the hand grip strength test and/or FTSTS. All patients were evaluated for disease staging (modified HY scale), quality of life, lower extremity strength (FTSTS) and hand grip strength during “on” phases.

Assessment of falls

A fall was defined as an event where the patient inadvertently came to the ground or other lower level that was not a result of a violent behavior such as fight, car or bike accident, syncope or epilepsy. The patients were asked about experiencing such an event in the six months prior to their medical visit. Information of falls obtained from the patients was cross-checked with data from relatives, caregivers and clinical records for accuracy.

Statistical analysis

For numerical variables, data were presented as means, standard deviations and medians. For categorical variables, data were described as frequencies and prevalence rates to investigate associations between risk factors and probable sarcopenia and falls. For the analysis of the participants’ characteristics, we used the Mann-Whitney U-test because independent variables were not normally distributed. To investigate the association between categorical variables, we used Pearson's chi-square and Fisher's exact tests. Logistic regression models including probable sarcopenia and falls as outcomes were adjusted for the variables with p < 0.05 in the bivariate analysis.

A significance level of 5% was adopted. Statistical analyses were performed using the JAMOVI statistical software (Version 0.9).

Results

Associations with probable sarcopenia

The study population was composed of a total of 218 patients, of which 93 (42.7%) were women. The mean age was 67.2 ± 10.9 years and mean disease duration was 9.4 ± 6.9 years. One hundred and twenty-one patients (55.5%) screened positive for sarcopenia using the SARC-F and 103 (47.4%) met the criteria for probable sarcopenia. Among patients with probable sarcopenia, 61 (59.2%) and 87 (84.4%) had low muscle strength according to hand grip strength and FTSTS respectively. Table 1 shows clinical and sociodemographic characteristics of the study population and the results from the bivariate analysis for probable sarcopenia.

Table 1

Sociodemographic and clinical characteristics and results from the bivariate analysis for probable sarcopenia.

	Probable sarcopenia
	Total	Yes	No	p
SARC-F+ a	121 (55,5%)	103 (100%)	18 (15,7%)	<0,001d
Gender				0,013c
Female	93 (42,7%)	53 (51,5%)	40 (34,8%)
Male	125 (57,3%)	50 (48,5%)	75 (65,2%)
Age	67.9 (59.8–75.6)	70.4 (59.9–76.8)	66.4 (59.4–73.6)	0,116b
Disease duration	7 (4–13)	9 (5–14)	6 (3–11)	0,009b
Hoehn and Yahr stage	2.5 (2–3)	3 (2–3)	2 (2–2.5)	<0,001b
SE ADS score	80 (70–90)	80 (60–90)	90 (80–90)	<0,001b
LED	1000 (600–1400)	1125 (750–1449)	900 (500–1398)	0,029b
Number of medications	4 (3–6)	5 (3–7)	4 (3–5)	0,032b
Polypharmacy				0,151c
<5	117 (53,7%)	50 (48,5%)	67 (58,3%)
≥5	101 (46,3%)	53 (51,5%)	48 (41,7%)
Hypertension	91 (41,7%)	43 (41,7%)	48 (41,7%)	0,999c
Type 2 DM	42 (19,4%)	23 (22,3%)	19 (16,7%)	0,292c
Dementia	27 (12,4%)	17 (16,5%)	10 (8,7%)	0,081c
Depression	100 (46,1%)	57 (55,3%)	43 (37,7%)	0,009c
Falls	92 (43,8%)	51 (51,5%)	41 (36,9%)	0,034c
GDS score	6 (3–9)	7 (4–10)	4 (2–7)	<0,001b
Motor physical therapy	24 (12%)	13 (13,5%)	11 (10,6%)	0,519c
Osteoporosis	21 (10%)	16 (16%)	5 (4,5%)	0,006c
PDQ score	40.4 (27.2–54.8)	51.3 (38.5–62.2)	31.4 (22.4–45.5)	<0,001b
Functional mobility	47.5 (22.5–72.5)	65 (42.5–80)	30 (15–50)	<0,001b
Activities of daily living	41.7 (25–62.5)	54.2 (33.3–75)	33.3 (16.7–45.8)	<0,001b
Emotional well-being	41.7 (25–58.3)	45.8 (33.3–66.7)	37.5 (25–50)	0,001b
Stigma	31.3 (21.9–56.3)	37.5 (25–68.8)	25 (18.8–43.8)	0,070b
Social support	58.3 (41.7–66.7)	58.3 (41.7–66.7)	58.3 (41.7–66.7)	0,832b
Cognition	37.5 (21.9–50)	43.8 (25–56.3)	25 (12.5–50)	<0,001b
Communication	33.3 (16.7–58.3)	41.7 (25–58.3)	25 (16.7–41.7)	0,002b
Bodily discomfort	50 (33.3–70.8)	58.3 (41.7–83.3)	50 (25–66.7)	0,001b
Hand grip strength	21.3 (15–30.6)	18 (12–25)	26.7 (18.8–34.3)	<0,001b
FTSTS				<0,001b
Altered	144 (66,1%)	95 (92,2%)	49 (42,6%)
Not performed	17 (7,8%)	6 (5,8%)	11 (9,6%)
Normal	57 (26,1%)	2 (1,9%)	55 (47,8%)

Data expressed in percentage (%), as well as mean ± standard deviation for normally distributed data and median (25th-75th) for not normally distributed

a: Sarcopenia was assessed using SARC-F scores, SARC-F +: score ≥4.

b: Mann-Whitney test

c: Pearson's chi-squared test

d: Fisher's Exact Test

SE ADL: Schwab and England Activities of Daily Living Scale; LED: levodopa equivalent dose; GDS: Geriatric Depression Scale; PDQ: Parkinson’s Disease Questionnaire; Type 2 DM: Type 2 diabetes mellitus; FTSTS: Five Times Sit-to-Stand test.

The following variables with p < 0.05 in the bivariate analysis were included in the logistic regression models: gender, falls, osteoporosis, depression, GDS score, modified HY stage, SE ADL score, LED, disease duration, number of medications and PDQ-39 score. These variables were included in the logistic regression models in a stepwise forward manner. Female gender, modified HY stage and PDQ-39 score were independently significantly associated with probable sarcopenia (Table 2).

Table 2

Multivariate analysis for probable sarcopenia.

Predictors	OR (95% CI)	p-value
Female gender	3.05 (1.34–6.94)	0.008
Hoehn and Yahr stage	1.87 (1.06–3.29)	0.03
PDQ score	1.06 (1.03–1.09)	<0.001

Stepwise-forward logistic regression models for probable sarcopenia. Variables included in the regression analysis: gender; falls; osteoporosis; Hoehn and Yahr stage; SE ADL: Schwab and England Activities of Daily Living Scale; LED: levodopa equivalent dose; disease duration; and PDQ score: Parkinson’s Disease Questionnaire.

Associations with falls

Disease duration, modified HY stage, SE ADL score, LED, probable sarcopenia and positive SARC-F (SARC-F+) were associated with falls with p < 0.05 in the bivariate analysis (Table 3).

Table 3

Sociodemographic and clinical characteristics and results from the bivariate analysis for falls.

	Falls
	Total	Yes	No	p-value
SARC-F+ a	115 (54.8%)	62 (67.4%)	53 (44.9%)	<0.001c
Gender				0.518c
Female	92 (43.8%)	38 (41.3%)	54 (45.8%)
Male	118 (56.2%)	54 (58.7%)	64 (54.2%)
Age	67.9 (59.8–75.6)	69 (61.6–73.8)	66.9 (57.8–76.8)	0.632b
Disease duration	7 (4–13)	10 (5–17.5)	6 (4–10)	<0.001b
Hoehn and Yahr stage	2.5 (2–3)	2.8 (2–3)	2 (2–2.5)	0.001b
SE ADL score	80 (70–90)	80 (70–90)	90 (80–90)	0.016b
LED	1000 (600–1400)	1125 (712.5–1524.5)	900 (550–1350)	0.024b
Number of medications	4 (3–6)	5 (3–7)	4 (3–6)	0.052b
Polypharmacy				0.065c
<5	111 (52.9%)	42 (45.7%)	69 (58.5%)
≥5	99 (47.1%)	50 (54.3%)	49 (41.5%)
Hypertension	87 (41.4%)	33 (35.9%)	54 (45.8%)	0.149c
Type 2 DM	41 (19.6%)	20 (21.7%)	21 (17.9%)	0.493c
Dementia	26 (12.4%)	15 (16.3%)	11 (9.3%)	0.127c
Depression	97 (46.4%)	43 (47.3%)	54 (45.8%)	0.830c
Probable sarcopenia	99 (47.1%)	51 (55.4%)	48 (40.7%)	0.034c
Katz scale score	2.3 ± 1.5 (2)	2.4 ± 1.4 (2)	2.3 ± 1.6 (2)	0.446b
Pfeffer scale score	9.6 ± 7.3 (8)	9.6 ± 7.1 (9)	9.6 ± 7.5 (8)	0.989b
GDS score	6 (3–9)	6 (4–9)	5 (3–8)	0.573b
Motor physical therapy	24 (12.3%)	13 (15.5%)	11 (9.9%)	0.241c
Osteoporosis	21 (10.4%)	9 (10%)	12 (10.7%)	0.869c
PDQ score	40.4 (27.2–55.1)	43.6 (27.6–60.3)	39.1 (26.9–51.3)	0.149b
Functional mobility	47.5 (22.5–72.5)	46.3 (25–77.5)	47.5 (22.5–70)	0.532b
Activities of daily living	41.7 (25–62.5)	43.8 (25–70.8)	37.5 (25–58.3)	0.152b
Emotional well-being	41.7 (25–58.3)	41.7 (25–62.5)	37.5 (25–58.3)	0.340b
Stigma	31.3 (18.8–56.3)	31.3 (25–68.8)	31.3 (12.5–50)	0.169b
Social support	58.3 (41.7–66.7)	58.3 (41.7–66.7)	58.3 (41.7–66.7)	0.938b
Cognition	37.5 (21.9–50)	37.5 (25–56.3)	37.5 (18.8–50)	0.414b
Communication	33.3 (16.7–58.3)	33.3 (25–58.3)	33.3 (16.7–58.3)	0.362b
Bodily discomfort	50 (33.3–75)	54.2 (41.7–75)	50 (33.3–70.8)	0.296b
Hand grip strength	21.7 (15–30.6)	21.3 (14.7–28.7)	22 (15.3–32.7)	0.291b
FTSTS				0.067c
Altered	141 (67.1%)	62 (67.4%)	79 (66.9%)
Not performed	16 (7.6%)	11 (12%)	5 (4.2%)
Normal	53 (25.2%)	19 (20.7%)	34 (28.8%)

Data expressed in percentage (%), as well as mean ± standard deviation for normally distributed data and median (25th-75th) for not normally distributed

a: Sarcopenia was assessed using SARC-F scores, SARC-F +: score ≥4.

b: Mann-Whitney test

c: Pearson's chi-squared test

d: Fisher's Exact Test; SE ADL: Schwab and England Activities of Daily Living Scale; LED: levodopa equivalent dose; GDS: Geriatric Depression Scale; PDQ: Parkinson’s Disease Questionnaire; Type 2 DM: Type 2 diabetes mellitus; FTSTS: Five Times Sit-to-Stand test.

These variables were included in the stepwise forward logistic regression models. Table 4 shows that only SARC-F+ and disease duration were independently associated with falls in our study. The association between positive SARC-F and occurrence of falls is also illustrated in Fig 1.

Table 4

Multivariate analysis for falls.

Predictors	OR (95% CI)	p-value
SARC-f+	1.87 (1.02–3.41)	0.042
Duration of disease	1.10 (1.05–1.15)	<0.001

Stepwise-forward logistic regression models for falls. Variables included in regression: disease duration; Hoehn and Yahr stage; SE ADL: Schwab and England Activities of Daily Living Scale; LED: levodopa equivalent dose; probable sarcopenia; and SARC-F+

Fig 1

Association between positive SARC-F and occurrence of falls.

Discussion

In our study, we found a very high prevalence of sarcopenia in PD patients (47.4%). Recent systematic review and meta-analysis of population-based studies estimated an overall prevalence of sarcopenia of 10% in healthy adults aged ≥60 years [2] and a previous report of the International Sarcopenia Initiative have found a prevalence varying between 1% and 29% in community-dwelling populations aged ≥50 years [22].

There are possible explanations for this higher prevalence of sarcopenia in PD patients. Firstly, the decrease in the numbers of motoneurons is a common feature in sarcopenia and PD. The strength for movement is secondary to contraction induced by neural action potentials. Dopaminergic action that facilitates the movement is compromised in PD so that both sarcopenia and PD have overlapping pathophysiological mechanisms for muscle fiber loss: inflammation, muscle autophagy, oxidative stress, and apoptosis [6]. Secondly, the loss of lean mass secondary to malnutrition is also prevalent in PD. PD patients are likely to experience nausea, dyspepsia, constipation, medication side effects, dysphagia, anorexia and depressive symptoms that cause reduced energy intake [23]. Thirdly, it has also been found that PD patients have lower levels of physical activity (in terms of amount and intensity) compared to healthy older adults [5,7,24].

To date, few studies have assessed the prevalence of sarcopenia in PD patients, with reports ranging from 6% to 55.8% [8,9,25,26]. It should be noted that the prevalence of sarcopenia varies greatly due to the use of different definitions and diagnostic tools as well as patient selection methods. However, these data are of great relevance given the increased risk of adverse outcomes associated with sarcopenia in the older adults such as falls, fractures and impaired ability to perform ADL [19], which are also important issues when managing PD patients.

Patients with probable sarcopenia and falls show higher modified HY and lower SE ADL scores. Moreover, they take higher LED and use a greater number of medications. It has been shown that older people with antiparkinsonian drugs are at higher risk of being exposed to fall-risk inducing drugs [27] The more advanced the disease, the more they require medications and the less independent these patients are [28]. As neurodegeneration progresses, body composition and physical performance are affected. Weight loss is very common in later PD stages and underweight patients show severe reductions in muscle quality and quantity [6].

Probable sarcopenia was significantly strongly associated with depression and higher GDS-15 scores. This association can be explained by physical inactivity, upregulation of inflammatory cytokines and dysregulation of hormones in the hypothalamic–pituitary–adrenal axis. A recent systematic review and meta-analysis of 10 observational studies concluded that sarcopenia was independently associated with depression [29].

Probable sarcopenia was associated with falls. Several studies have showed that reduced mobility, poor balance and reduced leg muscle strength have been associated with increased fall risk [30-31]. These signs are clinical manifestations of sarcopenia.

Disease duration, quality of life and female gender were independently associated with sarcopenia in this study. Evidence in the literature of factors associated with sarcopenia in PD patients is still scarce. In a recent cross-sectional study including 104 PD patients from a tertiary center in Innsbruck, Austria, sarcopenia was significantly associated with longer disease duration among other factors [9]. It suggests that, in addition to its high prevalence in this population, sarcopenia might be associated with factors related to disease progression. Reduced quality of life is a very important long-term adverse outcome. Furthermore, patients’ quality of life was assessed in our study using the PDQ-39, which is a questionnaire that takes into account patient self-reports and observation. Thus, the association with reduced quality of life emphasizes that active case finding, diagnosis and proper management of sarcopenia in PD patients is essential. The association with female gender is controversial and it is not well established in the literature [9].

Falls in PD involve very complex multifactorial mechanisms and recurrent falls is a milestone of disease progression [32]. Falls were significantly more frequent in patients who were screened positive in the SARC-F compared to those screened negative. SARC-F is a very useful tool because it does not require special measurements or equipment as well as highly trained professionals for its administration. It is used to identify older adults with impaired physical function since it is a proven good predictive tool of physical limitations and mortality in community-dwelling older people [11]. The five items of SARC-F indirectly assess the risk of falls through muscle strength and balance. Tan et (2017) al. managed to identify 93% of patients at increased risk of adverse outcomes and care burden from falls using the SARC-F screening tool [33]. SARC-F is a questionnaire that is self-reported by the patient and reflects how much difficulty they face with ADL. Indeed, Almeida et al. (2015) identified self-reported disability as the strongest predictor of falls in a sample of 130 patients in a 12-month prospective study conducted in Bahia, Brazil [3].

Disease duration was associated with falls in the multivariate regression model in this study. Farombi et al. (2016) evaluated 81 PD patients and compared fallers versus non-fallers and showed that frequent fallers had significantly worse outcomes and longer disease duration [4]. PD symptoms are progressive and affect postural control in advanced stages and longer disease duration is associated with greater disease severity. Disease duration has also been correlated with the occurrence of falls in other studies [34].

The present study has some limitations. Firstly, we excluded patients who were wheelchair users. Therefore, the prevalence of sarcopenia may have been underestimated in our study population. Secondly, curves of normality and cut-off points for muscle mass and function to assess sarcopenia in PD are not available yet. In addition, low muscle mass was not measured by dual-energy X-ray absorptiometry (DXA) which is considered the gold standard for diagnosing this condition [35].

Thirdly, muscle strength testing in individuals with bradykinesia and rigidity is a subject of debate. Cano-de-la-cuerda et al (2010) [36] developed a systematic review with the objective of investigating whether muscle weakness exists in Parkinson's disease. Seventeen studies showed that the isokinetic muscle strength of patients with Parkinson's disease was reduced compared to age-matched controls. Interestingly, they concluded that muscle weakness was not specifically associated with tremor or stiffness. The specific etiology of this weakness requires further studies. It is necessary to establish better if this weakness is of central or peripheral origin, that is, if it is intrinsic to the disease or a secondary phenomenon. Duncan, Leddy and Earhart (2011) evaluated intra-rater and test-retest reliability of the FTSTS, the performance of patients in the test at different stages of the disease, its correlation to other measures and its ability to predict falls in 80 patients with PD [20]. They concluded that the test-retest reliability of the FTSTS in PD is excellent and it is comparable to that of other populations. They recommended the use of the FTSTS as a quick and objective measure to determine the risk of fall. The FTSTS was correlated to worse quality of live, to lower balance confidence, to lower limbs strength, to slower movements of upper extremity in bivariate analysis. The lower limbs strength was not correlated to FTSTS in multiple regression analysis. To the best of our knowledge, it was the first trial to examine FTSTS performance in individuals with PD. The sample size of the study was small so that we need more studies that examine the FTSTS in individuals with PD to clarify its correlation with postural instability and bradykinesia. PD asymmetry should be considered, and bradykinesia, rigidity and tremor may be present unilaterally or bilaterally and one side is usually more affected. This is why we used greater hand grip strength, as suggested by Vetrano et al. (2018) [6], instead of grip strength of dominant hand, as recommended by the sarcopenia consensus [22]. Rising from a chair is a physically demanding function that can be compromised by muscle quality and PD symptoms.

Yet, our study has some strengths. The study’s main finding of an increased prevalence of probable sarcopenia in PD suggests the presence of neurodegenerative processes leading to sarcopenia. We showed that a simple inexpensive tool (SARC-F) is associated with occurrence of falls. The value of SARC-F as a predictive tool should be further investigated in prospective studies. In addition, we highlighted the impact of probable sarcopenia on quality of life. Sarcopenia and falls pose an economic burden to our societies [22], yet an inexpensive intervention approach including high-protein diet and resistance exercise training can help reverse or improve this condition. The sooner these interventions are implemented, the more likely PD patients will benefit from them.

Conclusions

Despite its clinical importance, sarcopenia diagnosis in PD patients has not been much explored in clinical practice. It is necessary to optimize the assessment of PD patients including body composition and mass and muscle strength assessments for the diagnosis of sarcopenia. Sarcopenia and PD share common pathways and, regardless of their source, they may affect each other’s prognosis and patients’ quality of life. The results of our study support the use of SARC-F for screening fall risk. We plan to further investigate sarcopenia and SARC-F as predictors of falls in a future prospective study.

20 Jan 2020

PONE-D-19-34534

Clinical correlates of sarcopenia and falls in Parkinson’s disease

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1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: No

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: No

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: I have read the tex with great interest. SARC-F works well in PD patients. Study is well organized. Clinical confaunders are comprehensively evaluated. I have some suggestions in the content of minör revision.

Abstract

Falls are mentioned in the method section as ‘’in the six months prior to their medical visit’’. This description is sufficient throughout the abstract section. Please remove this description after each ‘’falls’’ from result section.

Introduction

Line 68: Despite its importance, few studies have assessed the prevalence and characteristics of sarcopenia in this population (references?). Please add refrences.

Line 80: on the quality of life ‘’of’’ PD patients. Please write ‘’in’’ instead of ‘’of’’.

Materials and Metods

Please define how you diagnosed dementia and osteoporosis.

Line 137:’’ lower extremity strength (SARC-F) and strength during on phases.’’ Please change as ’’lower extremity strength (FTSTS) and hand grip strength during on phases.’’

Line 142: Information ‘’on the number’’ of falls. Please remove ‘’on the number’’ because you did not evaluate the recurrent falls.

Falls are mentioned in the method section as ‘’in the six months prior to their medical visit’’. This description is sufficient throughout the text. Please remove this description after each ‘’falls’’ from result and discussion sections.

Results

Line 164: Before defining Table 1 please give the number (%) of patients with low muscle strenght according to both hand grip strenght and FTSTS.

Line 190: Why did you not include depression or GDS scores and number of medications in logistic regression models because p <0.05 in these values? Also please define depression cut off point according to GDS scale in method section.

In Table 1 and 3 both median and mean±standart deviation are not necessary, please only give mean±standart for normally distributed data and give median (25th-75th) for not normally distributed.

In Table 1 and 3 total number of participants for each independent variable is not necessary. You can remove them. (Example: SARC-F+ a ‘’(n = 218)’’ is not necessary)

Table 4: Instead of ‘’time’’ please write ‘’duration’’ of disease

Discussion

Line 305: Disease duration was associated ‘’to’’ falls. Please write ‘’with’’ instead of ‘’to’’.

Line 307: ‘’compared falling versus non-falling’’ please change the statement as ‘’compared fallers versus non-fallers’’

Line 310: Disease duration has also been correlated ‘’to’’ the occurrence of falls in other studies. Please write ‘’with’’ instead of ‘’to’’.

References

There is a duplication of references. 6th and 15th are same.

Reviewer #2: Dear Authors

the main problem with the manuscript is regarding the diagnosis and definition of sarcopenia.

Using the time to rise from a chair in Parkinsonian patients the main limitation is that time is related to the brakinesia and not to the muscle function. Other tests should be used in this case for the diagnosis of sarcopenia

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6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Firuzan Fırat Ozer

Reviewer #2: Yes: Fulvio Lauretani

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17 Feb 2020

Reviewer #1:

I have read the text with great interest. SARC-F works well in PD patients. Study is well organized. Clinical confounders are comprehensively evaluated. I have some suggestions in the content of minor revision.

Response: We thank the reviewer for the comments.

Abstract

Falls are mentioned in the method section as ‘’in the six months prior to their medical visit’’. This description is sufficient throughout the abstract section. Please remove this description after each ‘’falls’’ from result section.

Response: The description was further removed throughout the abstract section, as suggested.

Introduction

Line 68: Despite its importance, few studies have assessed the prevalence and characteristics of sarcopenia in this population (references?). Please add references.

Response: References are now added to this sentence.

Line 80: on the quality of life ‘’of’’ PD patients. Please write ‘’in’’ instead of ‘’of’’.

Materials and Metods

Response: We agree with the reviewer. The sentence was modified in accordance with the recommendations.

Please define how you diagnosed dementia and osteoporosis

Response: Dementia was diagnosed following the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) criteria (called major neurocognitive disorder). The diagnostic assessment for osteoporosis was conducted according to National Osteoporosis Foundation recommendations. This information was included in Methods section.

Line 137:’’ lower extremity strength (SARC-F) and strength during on phases.’’ Please change as ’’lower extremity strength (FTSTS) and hand grip strength during on phases.’’

Line 142: Information ‘’on the number’’ of falls. Please remove ‘’on the number’’ because you did not evaluate the recurrent falls.

Falls are mentioned in the method section as ‘’in the six months prior to their medical visit’’. This description is sufficient throughout the text. Please remove this description after each ‘’falls’’ from result and discussion sections.

Response: We thank the reviewer for the suggestions. All modifications were performed according to the reviewer suggestions.

Results

Line 164: Before defining Table 1 please give the number (%) of patients with low muscle strenght according to both hand grip strenght and FTSTS.

Response: Among patients with probable sarcopenia, 61 (59.2%) and 87 (84.4%) had low muscle strength according to hand grip strength and FTSTS respectively. We included this information in Results section.

Line 190: Why did you not include depression or GDS scores and number of medications in logistic regression models because p <0.05 in these values?

Depression, GDS score and number of medications were in fact included in logistic regression models. This information is now included in Results section.

Also please define depression cut off point according to GDS scale in method section.

Response: Although GDS was applied in this study, it was not used in order to establish a diagnosis of depression, which was defined according to DSM-V criteria. In this sense, a cut off point for GDS was not adopted in this study.

In Table 1 and 3 both median and mean ± standart deviation are not necessary, please only give mean±standart for normally distributed data and give median (25th-75th) for not normally distributed.

In Table 1 and 3 total number of participants for each independent variable is not necessary. You can remove them. (Example: SARC-F+ a ‘’(n = 218)’’ is not necessary)

Table 4: Instead of ‘’time’’ please write ‘’duration’’ of disease

Discussion

Line 305: Disease duration was associated ‘’to’’ falls. Please write ‘’with’’ instead of ‘’to’’.

Line 307: ‘’compared falling versus non-falling’’ please change the statement as ‘’compared fallers versus non-fallers’’

Line 310: Disease duration has also been correlated ‘’to’’ the occurrence of falls in other studies. Please write ‘’with’’ instead of ‘’to’’.

Response: We thank the reviewer for the suggestions. All modifications were performed according to the reviewer suggestions.

References

There is a duplication of references. 6th and 15th are same.

Response: We apologize the reviewer for this mistake. All References section was changed considering that and also because new references were added.

Reviewer #2:

Dear Authors:

The main problem with the manuscript is regarding the diagnosis and definition of sarcopenia.

Using the time to rise from a chair in Parkinsonian patients the main limitation is that time is related to the bradykinesia and not to the muscle function. Other tests should be used in this case for the diagnosis of sarcopenia

Response: The authors acknowledge the influence of bradykinesia on altered results in this test as a limitation of the study. The limitations regarding the Five Times Sit-to-Stand Test (FTSTS) are in the tenth paragraph of the discussion. Indeed, literature concerning diagnosis of sarcopenia in PD patients is extremely scarce. Nonetheless, the FTSTS is the only test recommended by the European Working Group on Sarcopenia in Older People (EWGSOP 2) to assess muscle strength of the lower limbs. In this sense, as a validated tool to assess probable sarcopenia due to reduced muscle strength in the lower limbs in PD patients is yet unavailable, and given the need to use a standardized approach, the authors decided to follow the most widely accepted recommendations. Moreover, in this study all patients were assessed during “on” phases in order to minimize this confounding factor.

Cano-de-la-cuerda et al (2010) developed a systematic review with the objective of investigating whether muscle weakness exists in Parkinson's disease. Seventeen studies showed that the isokinetic muscle strength of patients with Parkinson's disease was reduced compared to age-matched controls. Interestingly, they concluded that muscle weakness was not specifically associated with tremor or stiffness. The specific etiology of this weakness requires further studies. It is necessary to establish better if this weakness is of central or peripheral origin, that is, if it is intrinsic to the disease or a secondary phenomenon. Duncan, Leddy and Earhart (2011) evaluated intra-rater and test-retest reliability of the FTSTS, the performance of patients in the test at different stages of the disease, its correlation to other measures and its ability to predict falls in 80 patients with PD. They concluded that the test-retest reliability of the FTSTS in PD is feasible and it is comparable to that of other populations. They recommended the use of the FTSTS as a quick and objective measure to determine the risk of fall. The FTSTS was correlated to worse quality of live, to lower balance confidence, to lower limbs strength, to slower movements of upper extremity in bivariate analysis. The lower limbs strength was not correlated to FTSTS in multiple regression analysis. To the best of our knowledge, it was the first trial to examine FTSTS performance in individuals with PD. The sample size of the study was small so that we need more studies that examine the FTSTS in individuals with PD to clarify its correlation with postural instability and bradykinesia.

References

Cano-de-la-Cuerda R, Pérez-de-Heredia M, Miangolarra-Page JC, Munoz-Hellín E, Fernández-de-las-Penas C. Is there muscular weakness in Parkinson's disease?. American Journal of Physical Medicine & Rehabilitation. 2010;89(1):70-6. doi: 10.1097/PHM.0b013e3181a9ed9b.

Duncan RP, Leddy AL, Earhart GM. Five times sit-to-stand test performance in Parkinson's disease. Arch Phys Med Rehabil. 2011;92(9):1431-6. doi: 10.1016/j.apmr.2011.04.008.

Submitted filename: Response to reviewers Plos 2.16.2020.docx

Click here for additional data file.

26 Feb 2020

Clinical correlates of sarcopenia and falls in Parkinson’s disease

PONE-D-19-34534R1

Dear Dr. Lima,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

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If your institution or institutions have a press office, please notify them about your upcoming paper to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

With kind regards,

Masaki Mogi

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

No further comment.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #2: The authors addressed all my comments. In particular, they reported the validity of using the time to reach from a chair in PD.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Firuzan Fırat Ozer

Reviewer #2: Yes: Fulvio Lauretani

5 Mar 2020

PONE-D-19-34534R1

Clinical correlates of sarcopenia and falls in Parkinson’s disease

Dear Dr. Lima:

I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

For any other questions or concerns, please email plosone@plos.org.

Thank you for submitting your work to PLOS ONE.

With kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Masaki Mogi

Academic Editor

PLOS ONE