Incident mobility disability, parkinsonism, and mortality in community-dwelling older adults

Shahram Oveisgharan; Lei Yu; David A Bennett; Aron S Buchman

doi:10.1371/journal.pone.0246206

. 2021 Feb 3;16(2):e0246206. doi: 10.1371/journal.pone.0246206

Incident mobility disability, parkinsonism, and mortality in community-dwelling older adults

Shahram Oveisgharan ^1,^2,^*, Lei Yu ^1,², David A Bennett ^1,², Aron S Buchman ^1,²

Editor: Stephen D Ginsberg³

PMCID: PMC7857621 PMID: 33534811

Abstract

Background

Mobility disability and parkinsonism are associated with decreased survival in older adults. This study examined the transition from no motor impairment to mobility disability and parkinsonism and their associations with death.

Methods

867 community-dwelling older adults without mobility disability or parkinsonism at baseline were examined annually. Mobility disability was based on annual measured gait speed. Parkinsonism was based on the annual assessment of 26 items from the motor portion of the Unified Parkinson’s Disease Rating Scale. A multistate Cox model simultaneously examined the incidences of mobility disability and parkinsonism and their associations with death.

Results

Average age at baseline was 75 years old and 318 (37%) died during 10 years of follow-up. Mobility disability was almost 2-fold more common than parkinsonism. Some participants developed mobility disability alone (42%), or parkinsonism alone (5%), while many developed both (41%). Individuals with mobility disability or parkinsonism alone had an increased risk of death, but their risk was less than the risk in individuals with both impairments. The risk of death did not depend on the order in which impairments occurred.

Conclusion

The varied patterns of transitions from no motor impairment to motor impairment highlights the heterogeneity of late-life motor impairment and its contribution to survival. Further studies are needed to elucidate the underlying biology of these different transitions and how they might impact survival.

Introduction

Motor impairment is common and affects up to half or more of older adults [1–3] and is associated with diverse adverse health outcomes including death [4–6]. Impaired motor function in older adults is heterogeneous ranging from symptoms of poor strength, slowed walking, imbalance, reduced dexterity to motor disability. Investigators have developed a wide variety of clinical instruments that target the assessment of different motor abilities when testing motor function of older adults. For example, handgrip strength and gait speed performances are important features of several measures including sarcopenia and physical frailty. By contrast, parkinsonism focuses on other motor signs and symptoms, parkinsonian gait, tremor, rigidity and bradykinesia, which commonly manifest in older adults.

Many studies suggest that impairment of different motor phenotypes is associated with reduced survival, but few studies have examined the inter-relationship among multiple motor phenotypes and their association with survival in the same individuals [6–8]. Previously, we reported that gait speed and the severity of parkinsonism in the same individuals are independently related to risk of mortality [9]. These findings suggest that these two phenotypes are not duplicative, but rather may capture distinct facets of motor function that might explain why their combination is more strongly associated with risk of death than either alone. This prior study examined the association of continuous measures of these two motor phenotypes at one point in time with survival. Thus, it is unknown whether the risk of death varies as older adults without initial mobility disability or parkinsonism develop one or both of these motor impairments over time or if the order of the development of these impairments affects an individual’s risk of death. These knowledge gaps impede risk stratification of older adults and public health intervention efforts to reduce these common motor phenotypes and improve survival.

To fill these knowledge gaps, the current study employed a novel analytic method, used in some recent studies [10], to examine the relationship of mobility disability and parkinsonism and their relation to death. Specifically, we had four objectives. First, we estimated the incidence of the two phenotypes. Second, we tested the hypothesis that mobility disability increases the risk for parkinsonism and vice versa. Third, we examined whether incident mobility disability and incident parkinsonism, alone or together, was associated with the risk of death. Fourth, we examined whether the sequence of the occurrence of these disabilities was associated with the risk of death. We analyzed data from 867 community-dwelling older adults, participating in one of two community-based longitudinal studies, who were initially without mobility disability and parkinsonism and underwent repeated annual assessments.

Methods

Participants

The Religious Orders Study (ROS) began recruitment in 1994. The Rush Memory and Aging Project (MAP) began recruitment in 1997. Eligible participants in both studies were adults older than 65 years without known dementia, and both studies are ongoing. ROS recruits nuns, priests, and brothers across the United States. MAP recruits participants living in private homes, subsidized housings, and retirement facilities across the greater Chicago metropolitan area. Both studies employ harmonized data collection methods performed by the same staff, including participants’ consent to annual testing during life and to Anatomical Gift Act at the time of death. Harmonized data collection facilitates joint analyses of the studies’ data. Details of the studies are described elsewhere [11]. A Rush University Medical Center Institutional Review Board approved each study. Data from these studies can be obtained via requests uploaded to www.radc.rush.edu.

The analytic sample for the current study included participants without mobility disability and parkinsonism at baseline. As cognitive and motor impairment are related [12], we excluded participants with cognitive impairment at baseline. Of 1469 ROS participants recruited through October 2019, 1009 were without cognitive impairment at baseline, of whom 464 did not have either mobility disability or parkinsonism assessment and 236 had mobility disability or parkinsonism at baseline. From 309 participants without motor or cognitive impairment at baseline, 19 were lost to follow up that leaving 290 ROS participants for the current study.

Through October, 2019, 1484 of 2164 MAP participants were without cognitive impairment at baseline, 464 did not have either mobility disability or parkinsonism assessment and 236 had mobility disability or parkinsonism at baseline. Of 659 MAP participants without motor or cognitive impairment at baseline, 82 were lost to follow up leaving 577 adults for these analyses. The clinical characteristics for the 867 adults included in this study [MAP (577); ROS (290)] are summarized in Table 1.

Table 1. Baseline clinical characteristics based on final pattern of motor impairments developed during the study.

Covariates	All (n = 867)	NI (n = 110)^‡	MD (n = 362)^‡	PARK (n = 40)^‡	Park\|MD (n = 236)^‡	MD\|PARK (n = 119)^‡
Demographics
Age, years, mean (SD)	75.5 (7.4)^**	74.1 (7.3)	73.6 (7.5)	78.7 (6.6)	76.9 (7.0)	78.4 (6.5)
Female, n (%)	658 (76)	76 (69)	281 (78)	27 (68)	189 (80)	85 (71)
Education, years, mean (SD)	16.5 (3.5)^*	17.1 (3.6)	16.6 (3.4)	15.7 (3.3)	16.4 (3.5)	15.7 (3.4)
Chronic health conditions
Vascular risk factors and diseases
Hypertension, n (%)	403 (47)	52 (47)	166 (46)	20 (50)	113 (48)	52 (44)
Diabetes, n (%)	87 (10)^*	10 (9)	38 (11)	10 (25)	16 (7)	13 (11)
History of smoking, n (%)	297 (34)	41 (37)	128 (35)	13 (33)	77 (33)	38 (32)
Number of 3 vascular risk factors, mean (SD)	0.9 (0.8)	0.9 (0.8)	0.9 (0.8)	1.1 (0.9)	0.9 (0.8)	0.9 (0.8)
History of stroke, n (%)	43 (5)	5 (5)	16 (5)	2 (5)	13 (6)	7 (6)
History of myocardial infarction, n (%)	63 (7)	6 (5)	26 (7)	5 (13)	16 (7)	10 (8)
History of claudication, n (%)	40 (5)	1 (1)	18 (5)	1 (3)	15 (6)	5 (4)
Number of 3 vascular diseases, mean (SD)	0.2 (0.4)	0.1 (0.3)	0.2 (0.4)	0.2 (0.4)	0.2 (0.4)	0.2 (0.5)
Musculoskeletal pain (any joint), n (%)	331 (38)	33 (30)	133 (37)	13 (33)	107 (45)	45 (38)

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^‡NI: Remained without mobility impairment and parkinsonism during the study; MD: Developed only mobility disability; PARK: Developed only parkinsonism; PARK|MD: Developed parkinsonism following mobility disability; MD|PARK: Developed mobility disability following parkinsonism.

** P< 0.001.

^* P< 0.05.

Assessment of motor impairment

Assessment of mobility disability

Annual testing included a self-paced 8ft walking task. Although self-reported questionnaires are available for assessment of mobility disability, studies have shown objective measures like gait speed assessment to be a more sensitive and accurate method for identifying mobility disability [13, 14]. As previously published, incident mobility disability in these analyses was defined as the first visit at which measured walking speed was less than 0.55 m/s in the 8ft walk [15, 16].

Assessment of parkinsonism

Nurse clinicians assessed parkinsonian gait, rigidity, bradykinesia, and tremor annually using 26 items from a modified motor section of the original United Parkinson’s Disease Rating Scale (UPDRS) [17]. These measures have high inter-rater reliability and short-term stability among nurses and compared with a movement disorders specialist [18].

Four parkinsonian signs including parkinsonian gait, bradykinesia, rigidity, and tremor were assessed as described in prior publications [19–21]. A parkinsonian sign was present if two or more of the items assessed for that sign showed a mild abnormality. Incident parkinsonism was defined as the first visit at which two or more of the four parkinsonian signs were present. Clinical diagnosis of Parkinson’s disease (PD) was based on self-reported diagnosis of PD for which the participant received L-dopa or a dopamine agonist [21, 22].

Assessment of other clinical variables

Age was computed from self-report date of birth and date of baseline clinical assessment. Sex and years of education were recorded at study baseline. Self-report data at baseline also provided information about participants’ history of hypertension, diabetes, smoking, heart attack, stroke, lower extremities claudication, and joint pain.

The annual structured evaluation included administration of a battery of 17 cognitive tests. A neuropsychologist reviewed the cognitive tests’ results, and a physician with expertise in dementia reviewed annual findings including the summary of the neuropsychologist and classified the cognitive status of participants as no cognitive impairment, mild cognitive impairment, and dementia including probable and possible Alzheimer’s disease, according to established criteria [23]. In this study, we excluded participants whose cognitive status at the baseline was mild cognitive impairment (n = 895) or dementia (n = 212), or the cognitive status could not get determined (n = 33).

Statistical analyses

We employed a multi-state Cox model with six states to model the transition from no motor impairment to incident mobility disability and/or incident parkinsonism and finally to death [10]. All participants began with no motor impairment (NMI) at study baseline. The second to fifth states were intermediate states including: 2) incident mobility disability alone (MD); 3) incident parkinsonism alone (Park); 4) incident parkinsonism following mobility disability (Park|MD); 5) incident mobility disability following parkinsonism (MD|Park). The sixth state was the final absorbing state of death (Fig 1). The model structure included 9 distinct transitions as follows:

[\begin{matrix} N M I & M D & P a r k & P a r k | M D & M D | P a r k & D e a t h \\ N M I & - & λ_{12} (t | Z) & λ_{13} (t | Z) & - & - & λ_{16} (t | Z) \\ M D & - & - & - & λ_{24} (t | Z) & - & λ_{26} (t | Z) \\ P a r k & - & - & - & - & λ_{35} (t | Z) & λ_{36} (t | Z) \\ P a r k | M D & - & - & - & - & - & λ_{46} (t | Z) \\ M D | P a r k & - & - & - & - & - & λ_{56} (t | Z) \end{matrix}]

λ_ij(t|Z) is an estimate of the hazard of transition from state i to state j, and is modelled as the following:

λ_{i j} (t | Z) = λ_{i j, 0} (t) e x p (β_{i j}^{T} Z)

The λ_ij,0 is the baseline hazard, Z is the vector of covariates (including demographics and clinical variables), and β quantifies the association of Z with the hazard. In this study, we had nine hazard functions corresponding to the nine possible transitions. The model allows the associations of Z to be transition-specific.

Fig 1 — This figure illustrates the frequencies of participants in each of the six states and nine transitions examined in a multi-state model of incident mobility disability, parkinsonism, and death. All participants included in this study did not show mobility disability or parkinsonism at the analytic baseline. During the course of this study, nine paths for transition were possible between the baseline state of no motor impairment, four intermediate states of varying degrees of motor impairment, and the final absorbing state of death.

The main objective was to determine whether the sequence of occurrence of mobility disability and parkinsonism was associated with the risk of death. To accomplish this objective, we assumed proportional hazards of λ₄₆ and λ₅₆ as follows,

λ_{56} (t | Z) = λ_{46, 0} (t) e x p (β_{i 6}^{T} Z + δ)

The indicator δ tested the difference in the baseline hazard of death between MD|Park (i.e. mobility disability after Parkinsonism) and Park|MD (i.e. Parkinsonism after mobility disability). The proportional assumption was checked by using Schoenfeld residuals against the transformed time [24].

We took similar approach to examine whether the risk of impairment in either of the motor phenotypes was higher if impairment of the other phenotype had already occurred. We also examined whether risk of death was higher if either mobility disability alone, parkinsonism alone, or both impairments had developed compared to no prior motor impairment. The analyses were done using SAS/STAT software, version 9.4 (SAS Institute, Cary, NC, USA), and mstate package for R [25]. P values less than 0.05 was required to reject the null hypotheses.

Results

The 867 adults included in this study were on average 75 years old, and three fourth of them were women. During an average follow-up of 10 years (mean 10.2 yrs, SD = 5.2, range: 1–22), 318 (37%) died. As illustrated in Fig 1, individuals were classified into five different categories based on the presence or absence of motor impairment before death or the end of follow up. 1) Some participants remained without motor impairment (N = 110). Others transitioned into one of four states of motor impairment including: 2) mobility disability only (N = 362), 3) parkinsonism only (N = 40), 4) mobility disability and subsequently parkinsonism (N = 236), and 5) parkinsonism and subsequently mobility disability (N = 119). The baseline clinical characteristics and demographics for the entire analytic cohort and the five groups based on their final status of motor impairment are included in Table 1.

Incident mobility disability

Mobility disability occurred in 717 (83%) after an average 4.7 years (Fig 1). The risk of developing mobility disability was not different in participants who first developed parkinsonism compared to participants without motor impairment (p = 0.526). During five years of follow-up (Fig 2), an average participant (female 75 years old with 16 years of education) with or without parkinsonism showed an increased risk of developing mobility disability [Risk of mobility disability after 5 years: without prior parkinsonism: 36% (95% CI: 33% - 40%) versus prior parkinsonism: 34% (95% CI: 26% - 41%)].

Fig 2 — After five years, two average participants (female 75 years old with 16 years of education) without parkinsonism (red lines) and with parkinsonism (blue lines) show a similar risk for developing mobility disability of about 35%.

Incident parkinsonism

Parkinsonism occurred in about half (N = 395, 46%) of the participants after an average 5.3 years of follow up (Fig 1). Compared to participants without motor impairment, the risk of developing parkinsonism was higher in participants who first developed mobility disability (HR = 3.1, 95%CI: 2.5–4.0, p<0.001). This association persisted after controlling for age, sex, and education (HR = 2.6, 95%CI: 2.0–3.3, p<0.001).

Fig 3 illustrates the increased risk of developing parkinsonism in two average participants (female 75 years old with 16 years of education) with and without prior mobility disability. Over five years, the risk of developing parkinsonism is nearly 4-fold higher for a participant who first developed mobility disability, 39% (95% CI: 31% - 46%), compared to a participant without motor impairment 10% (95% CI: 8% - 12%).

Incident motor impairment and risk of death

Next we examined if the risk of death associated with incident mobility disability and incident parkinsonism were different. First, we examined whether the sequence of the occurrence of mobility disability and parkinsonism was associated with a different risk of death. The risk of death was not different in participants who developed mobility disability after first developing parkinsonism compared to participants who developed parkinsonism after first developing mobility disability (HR = 1.2, 95%CI: 0.9–1.6, p = 0.318).

Next, we compared the risk of death in the 3 groups of individuals who developed motor impairment prior to death (mobility disability alone, parkinsonism alone, and both mobility disability and parkinsonism) with a reference group of participants who did not develop motor impairment during the study. The risk of death was higher for all 3 groups of individuals who had developed motor impairment. For participants with incident mobility disability alone, the HR of death was 1.8 (95%CI: 1.2–2.6, p = 0.004). For participants with incident parkinsonism alone, the HR was 2.8 (95%CI: 1.7–4.7, p<0.001). For participants with both mobility disability and parkinsonism prior to death, the HR was 4.0 (95%CI: 2.7–5.9, p<0.001).

After controlling for demographics, incident motor impairment remained associated with the risk of death, but the association was attenuated: [incident mobility disability alone (HR = 1.5, 95%CI: 0.99–2.2, p = 0.059), incident parkinsonism alone (HR = 2.1, 95%CI: 1.3–3.5, p = 0.003), incident mobility disability and parkinsonism (HR = 2.5, 95%CI: 1.7–3.7, p<0.001)].

Fig 4 illustrates the estimated probability of death for four average participants (75 years old woman with 16 years of education) without and with different patterns of motor impairments prior to death. During 10 years of follow-up, the risk of death observed in individuals with both mobility and parkinsonism was almost two-fold higher compared to individuals without motor impairment. Risk of death was increased but intermediate for individuals with either mobility disability alone or parkinsonism alone.

Secondary analyses

We examined whether controlling for chronic health conditions attenuated the associations of incident motor impairments and the risk of death (S1–S3 Tables). Vascular risk factors were not associated with any of the 9 transitions. Vascular diseases increased the risk of death in participants who developed only mobility disability. Joint pain increased the risk of mobility disability in participants without any motor impairment. However, further adjustment for vascular diseases or joint pain did not change the inter-relationship of incident mobility disability and incident parkinsonism or their associations with risk of death (S4 and S5 Tables).

In further analyses, we explored whether inadequate power was responsible for the finding that incident mobility disability showed a trend for an association with death. The examined model had nine possible transitions compared to only two transitions in previous studies (Yes/No mobility disability and death) [26]. In a sensitivity analyses, we reduced the number of states and transitions, which increased the sample size per transition. In this model, the first state was the baseline state of NMI. The second, intermediate, state was incident mobility disability (with or without prior parkinsonism), and the final absorbing state was death (S1 Fig). As death could occur from baseline or from incident mobility disability, and participants could develop mobility disability during follow up without death, the model structure included 3 distinct transitions (S1 Fig, number of arrows). In this model with increased power due to the reduced transitions and states, mobility disability was a risk factor for death, even after controlling for age, sex, and education (HR = 1.5, 95%CI: 1.1–1.9, p = 0.008). The point estimate of the association of mobility disability and death was the same in the reduced (3 transitions) and the full (9 transitions) models, a finding that supports inadequate power to be responsible for the trend of association between mobility disability and death.

Parkinsonism is a heterogeneous syndrome including older adults receiving different medications, diverse medical conditions and degenerative disorders including PD. To ensure that our findings were not affected by a subset of individuals with PD, we excluded individuals with a clinical diagnosis of PD (n = 14) and repeated our analyses. Our primary findings were unchanged: mobility disability was a risk factor for incident parkinsonism and the highest risk of death was among participants with both mobility disability and parkinsonism (S2 Fig, S6 Table).

Of the four parkinsonian signs assessed in this study, bradykinesia is considered a cardinal sign for diagnosis of Parkinson disease. Therefore, to examine the robustness of our findings, we repeated our analyses after redefining incident parkinsonism based on the presence of bradykinesia together with at least another parkinsonian sign (tremor, rigidity, parkinsonian gait). Our primary findings showing that mobility disability increases the risk of parkinsonism and that individuals with both mobility disability and parkinsonism have the highest risk of death were unchanged (S3 Fig, S7 Table).

Discussion

This study employed novel modeling to simultaneously examine the transition from no motor impairment to one or both of incident mobility disability and parkinsonism, and whether these transitions were associated with different risks of death. We found that the transition from no motor impairment to motor impairment in older adults is more heterogeneous than currently appreciated. Some individuals may develop mobility disability or parkinsonism alone prior to death. However, these latter impairments represent an intermediate stage in many individuals as they eventually develop both impairments prior to death. A novel feature revealed by the transition state modeling was that both the frequency and the onset of incident mobility disability and incident parkinsonism during the study differed. Mobility disability was almost 2-fold more common than parkinsonism and the latter occurred later during follow-up. We found that both phenotypes are not uniformly associated with risk of death. While, individuals who developed either mobility disability or parkinsonism alone had an increased risk of death, parkinsonism was more strongly associated with death than mobility disability. However, the risk of death was the highest in individuals who developed both impairments but the order of their occurrence did not affect the increased risk of death. Together, these data suggest that mobility disability based on slowed gait speed and parkinsonism are related but distinct motor impairment phenotypes.

Many previous studies suggest that late-life motor impairment is associated with increased risk of adverse health outcomes, including death [5, 6, 8, 17]. However, late-life motor impairment is manifested by different motor phenotypes and most studies have focused on a single motor phenotype. In prior work, we reported that more severe parkinsonism is related to poor mobility in the same individuals and presence of both phenotypes is more strongly related to the risk of death [27]. These data were derived from standard survival models in which both phenotypes were measured at a single point in time, i.e., the analytic baseline [28]. These models cannot be used to assess intermediate state changes of the phenotype of interest or how a phenotype might be affected by other phenotype that may precede or follow its onset. To circumvent these limitations, we applied multistate modeling that was successfully employed in our prior study to examine the onset of incident cognitive impairment and incident mobility disability [10]. In the current study, application of the multistate modeling extended prior studies by examining incidence of one motor phenotype in relation to another, and their separate and joint associations with the risk of death.

We found that more than 80% of older adults developed mobility disability, based on slowed gait speed, prior to death, a finding that is congruent with prior survey studies reporting mobility impairment to be the most common type of disability in late-life [29]. In a previous study from the same cohort, we reported that isolated parkinsonian gait impairment was the most common isolated parkinsonian sign in older adults who went on to develop incident parkinsonism [20]. However, a slow gait is a motor phenotype that has a heterogenous group of risk factors including osteoarthritis and peripheral edema that are not risk factors for parkinsonism. In the current study, 60% of participants who developed mobility disability did not develop parkinsonism, a finding that suggests that in a large proportion of older adults mobility disability is not an early sign of parkinsonism. Gait speed may be slowed by numerous defects anywhere in the distributed motor control systems, which extend from the brain through the entire CNS to reach peripheral muscle. This may account in part for why gait speed is a robust, but non-specific early sign of diverse aging motor phenotypes and is not just an early sign of parkinsonism. As such, our data highlight a much more complex relationship between slowed gait speed and parkinsonism in older adults.

The differences observed with transition modeling between the temporal manifestations of mobility disability and parkinsonism were not merely descriptive but were associated with differences in their individual and joint associations with risk of death. These findings have important public health consequences with respect to risk stratification of older adults, emphasizing the importance of vigilance not only for incipient mobility disability, but also for the concurrence of parkinsonian signs. Moreover, the presence of both impairments as harbingers of an increased risk of death might be an important clinical indication for the necessity of more aggressive multi-modal lifestyle interventions and support to maintain survival in older adults.

It is unclear which factors account for the differences in the associations of mobility disability and parkinsonism with the risk of death. Prior studies have shown that more severe motor impairment in older adults is associated with a higher burden of age-related brain pathologies [12, 30] and more severe white matter hyperintensities [31, 32]. Therefore, individuals manifesting impairment of two rather than one motor phenotype may harbor a higher level of brain pathologies disrupting more components of motor networks. Further studies will be needed to elucidate the pathological bases of the findings in this study. Integrating brain imaging and multi-level omics data may help elucidate the underlying mechanisms that account for the patterns of progressive motor impairment observed in the current study.

Since this modeling approach examined nine transitions and six states, there was not enough power to examine additional phenotypes. For example, adding an additional phenotype such as cognitive impairment would increase the number of states from 6 to 17 and the transitions from 9 to 31. Moreover, we have examined the relationship between incident cognitive impairment, mobility disability and death in the current cohort in a prior publication [10]. We therefore excluded individuals with cognitive impairment at baseline to avoid confounding our results. To include additional phenotypes such as cognitive impairment or falls and to identify risk factors for transitions among these aging phenotypes, a larger study would be necessary.

The study has several strengths. Approximately 900 older adults were followed for an average of 10 years with a follow up rate of 90%. Uniform structured data collection was performed at the baseline and follow ups. We used validated instruments to assess two different motor phenotypes to categorize two types of motor impairment rather than using self-reported measures, minimizing recall bias. A novel multistate model was employed to simultaneously examine the onset and inter-relationship of both motor phenotypes as well as their individual and joint relationships to the risk of death.

However, the study has also limitations. Most of the participants were highly educated Caucasians underscoring the need to replicate the study findings in a more general population. Due to the number of transitions examined in the current study, we excluded participants with cognitive impairment that limits generalization of our study findings to the population with cognitive impairment. While the assessments by nurse clinicians have high inter-rater reliability and short term stability both among nurses and compared to a movement disorders specialist, participants were not assessed by a movement disorders specialist, which might have led to an underestimate of the prevalence of PD or atypical parkinsonism in the current study [18, 19]. Mobility disability was defined by a slow gait speed, rather than using more granular mobility metrics including sway score not collected longitudinally in this cohort, that may be less sensitive in capturing early stages of mobility impairment.

Supporting information

S1 Table. Association of vascular risk factors with mobility disability, parkinsonism, and death classified by the motor impairment status before the outcome.

(DOCX)

Click here for additional data file.^{(21.4KB, docx)}

S2 Table. Association of vascular diseases with mobility disability, parkinsonism, and death classified by the motor impairment status before the outcome.

(DOCX)

Click here for additional data file.^{(20.6KB, docx)}

S3 Table. Association of joint pain with mobility disability, parkinsonism, and death classified by the motor impairment status before the outcome.

(DOCX)

Click here for additional data file.^{(20.5KB, docx)}

S4 Table. Main findings of the study after further adjustment for vascular diseases.

(DOCX)

Click here for additional data file.^{(23.6KB, docx)}

S5 Table. Main findings of the study after further adjustment for joint pain.

(DOCX)

Click here for additional data file.^{(20.7KB, docx)}

S6 Table. Main findings of the study after exclusion of 14 participants who were diagnosed to have Parkinson disease during the study.

(DOCX)

Click here for additional data file.^{(20.6KB, docx)}

S7 Table. Main findings of the study after replacing parkinsonism with bradykinetic parkinsonism.

(DOCX)

Click here for additional data file.^{(20.9KB, docx)}

S1 Fig. States and transitions in a multi-state model of incident mobility disability and risk of death.

This figure describes a multi-state model of incident mobility disability and death. The boxes show the 3 possible states and the arrows show the 3 possible transitions.

(TIF)

Click here for additional data file.^{(60.7KB, tif)}

S2 Fig. States and transitions in a multi-state model of incident mobility disability, incident parkinsonism, and risk of death after exclusion of 14 participants with a diagnosis of Parkinson disease.

This figure illustrates the frequencies of participants in each of the six states and nine transitions examined in a multi-state model of incident mobility disability, bradykinetic parkinsonism, and death. Mobility disability was defined as gait speed less than 0.55 m/s in an 8-feet walk test. Parkinsonism was defined by presence of at least two of the four parkinsonian signs (bradykinesia, rigidity, tremor, parkinsonian gait). All participants included in this study were initially without mobility disability or parkinsonism at the analytic baseline. During the course of this study, nine paths for transition were possible between the baseline state of no motor impairment, four intermediate states of varying degrees of motor impairment, and the final absorbing state of death.

(TIF)

Click here for additional data file.^{(83.5KB, tif)}

S3 Fig. States and transitions in a multi-state model of incident mobility disability, incident bradykinetic parkinsonism, and risk of death.

This figure illustrates the frequencies of participants in each of the six states and nine transitions examined in a multi-state model of incident mobility disability, bradykinetic parkinsonism, and death. Mobility disability was defined as gait speed less than 0.55 m/s in an 8-feet walk test. Bradykinetic parkinsonism was defined as presence of bradykinesia and at least one other parkinsonian sign (which are rigidity, tremor, parkinsonian gait). All participants included in this study were initially without mobility disability or parkinsonism at the analytic baseline. During the course of this study, nine paths for transition were possible between the baseline state of no motor impairment, four intermediate states of varying degrees of motor impairment, and the final absorbing state of death.

(TIF)

Click here for additional data file.^{(83.6KB, tif)}

Acknowledgments

We thank participants of the Religious Orders Study and the Rush Memory and Aging project. Also, we appreciate Traci Colvin, MPH and Tracey Nowakowski, MA for study coordination, and other staff of the Rush Alzheimer’s Disease Center.

Data Availability

This study used data from the Rush Memory and Aging Project (R01AG17917) and the Rush Religious Orders Study (P30AG10161) obtained from the Rush Alzheimer's Disease Center (RADC) repository. The repository consent form signed by participants was approved and is overseen by the local Rush IRB. All of the data is available, but is governed by the data sharing plan for publicly sharing the RADC data repository that was approved by the local RUSH IRB and for which the participants consented. This plan was also approved by the primary funding agency, the NIA. The data underlying the results presented in this study can be requested at http://www.radc.rush.edu.

Funding Statement

This work was supported by National Institute of Health grants, R01AG043379, R01AG047679, R01AG056352, R01AG017917, RF1AG022018, R01NS078009, P30AG10161, and R01AG15819. We embrace that “The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.” In addition, authors received salary through the grants supported by National Institute of Health.

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PLoS One. doi: 10.1371/journal.pone.0246206.r001

Decision Letter 0

Stephen D Ginsberg

10 Sep 2020

PONE-D-20-20718

Incident mobility disability, parkinsonism, and mortality in community-dwelling older adults.

PLOS ONE

Dear Dr. Oveisgharan,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration by 3 Reviewers and an Academic Editor, all of the critiques of all three Reviewers must be addressed in detail in a revision to determine publication status. If you are prepared to undertake the work required, I would be pleased to reconsider my decision, but revision of the original submission without directly addressing the critiques of the 3 Reviewers does not guarantee acceptance for publication in PLOS ONE. If the authors do not feel that the queries can be addressed, please consider submitting to another publication medium. A revised submission will be sent out for re-review. The authors are urged to have the manuscript given a hard copyedit for syntax and grammar.

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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5. Review Comments to the Author

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Reviewer #1: This is an interesting and very long (10 years) follow-up study of more than 800 elderly people looking at the onset of Parkinosnism and mobiolity disorder according to clinicalle realistic definitions basen on objective clinical scales/measurements. A mathematical modelling approach (multi state Cox model) was applied to model the transition from no motor impairment to the two single impairments and the two different sequences of both impairments and their relation to the probablity of death. Probably the most interesting finding is the higher probabality to develop Parkinsonism after having developed mobility disorder whereas the probablility to develop mobility diosorder after having devlopped Parkinsonism is not much increased. The increased death probabalility with both mobility disorders and its increase with a combindation of both is not very surprising.

My main concern is the clinical meaning of this study. What do the data tell us? Can we conclude anything for screening or caring for the elderly based on this data?

I would suggest to shorten the disuccusion which in large parts repeats the results and try to allude to these questions if notpossible with the presented data give an outlook on how such analyses could help with this in the future.

Does the finding of the clearly increased riks to davalop Parkinsonism after having devleopped mobility impairment mean that slowing oft gait is an underrecognized early sign of Parkinsonism??

Also table 1 (which is difficult to read, the legend doe not state what is given outside and inside the brackets) could possibly give interesting clinical clues, Could the numbers on other diseases or symptoms give insights into risk factors for the two mobility impairments under study? or were there surprises as some expected rsik factors did not show up here??? Why is that?

Reviewer #2: This manuscript focuses on motor impairment with aging at the population level and association with mortality. Using 2 robust cohorts with long follow-up periods up to 10 years, the authors evaluated the impact of “mobility disability” (aka walking speed) and “parkinsonism” on one another and on risk of death. The manuscript is clear and addresses each of the 4 aims adequately. The main findings are that mobility disability is more common than parkinsonism, that each increases risk of death somewhat (parkinsonism more so than mobility disability) but that having both increases the risk of death even further. Developing parkinsonism does not increase the risk of developing mobility disability, but developing mobility disability does increase the risk of developing parkinsonism. However, the sequence did not impact mortality.

I have some conceptual concerns about the authors employing these two “motor phenotypes.” “Mobility disability” has a clear-cut definition and indicates walking speed. This is a heterogeneous group, as walking speed is often impacted by musculoskeletal issues, peripheral edema and neuropathy, and other conditions that are common with aging. “Parkinsonism” as defined here, is based on UPDRS rating but does not comply with clinical criteria for Parkinson’s disease (bradykinesia plus one of the following- tremor, rigidity, characteristic gait changes) and was determined by trained nurses rather than a movement disorders specialist. It seems possible therefore that participants with other forms of gait disorders that share certain features with PD could be misclassified, and that having either tremor (also very non-specific at this age) or rigidity could then lead to classification as parkinsonism. I understand that the goal of the work was not to diagnose PD, but these distinctions impact how we think about the results in terms of mechanisms and guidance for screening methodologies. To illustrate this, one interpretation of the results is that “mobility disability” represents a prodromal stage of parkinsonism with similar underlying neurobiology, but another interpretation is that as slow gait progresses it can mimic parkinsonian gait. Potential suggestions to address these uncertainties would be

1) sensitivity analysis with “parkinsonism” defined as bradykinesia score > 2 and one other feature,

2) add information if available on whether any participants were diagnosed clinically with PD.

One additional consideration worth mention in the discussion is that if participants were diagnosed clinically with PD, they may have been started on symptomatic medications that would impact their gait speed. If this information is available it would be helpful to include it.

Finally, it is very important to emphasize the participants with cognitive impairment were excluded. As the authors mention, cognition and gait are closely related, and thus the findings of this manuscript may not apply to the general population. The authors should also state how cognitive impairment was defined, to clarify the potential cognitive range of participants that were excluded.

Reviewer #3: Well-structured follow ups are a strength of this study as well as use of a multistate model to simultaneously examine incidence of mobility disability and Parkinsonism and their relationship to risk of death. Use of just gait speed for mobility disability may be one of the limitations of this study as previous studies have shown that longitudinal monitoring of postural sway may yield early detection of progressive motor decline. Measures of postural sway during quiet standing are often used to characterize postural control. (Horak F. B. (2006). Postural orientation and equilibrium: what do we need to know about neural control of balance to prevent falls? Age Ageing 35, 7–11. 10.1093/ageing/afl077)

Other risk factors that could contribute to balance control are specific vestibular deficits, somatosensory and visual deficits that should be taken in to account as risk factors for falls in elderly.

Survival is less in atypical parkinsonian syndromes. Also falls, postural instability are more common in these patients. Where these patients diagnosed by a movement disorders specialist and were you able to further characterize the parkinsonian syndrome? In line with this comment, in line 205-207 you talk about risk of death association in participants who developed mobility disability first or parkinsonism first and that the risk was not different between the two group. Again it is interesting to examine what percentage of these patients had typical vs atypical parkinsonism.

You mentioned that you have excluded the patients who had cognitive impairment at baseline. Did you continue to evaluate cognitive function longitudinally? Previous studies have shown a relationship between worsening of balance and cognitive decline. Day-to-Day Variability of Postural Sway and Its Association With Cognitive Function in Older Adults: A Pilot Study. Julia M. Leach,1,2,3,* Martina Mancini,4 Jeffrey A. Kaye,2,3,5,6 Tamara L. Hayes,2,3 and Fay B. Horak4,6

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PLoS One. 2021 Feb 3;16(2):e0246206. doi: 10.1371/journal.pone.0246206.r002

Author response to Decision Letter 0

31 Dec 2020

Dear Dr. Ginsberg

Thank you for the opportunity to revise and resubmit our manuscript. We appreciate the time and expertise of you and the reviewers for the careful reading and helpful comments. A point by point response to each comment is included below. Material changes to the manuscript, including the changes’ locations, are noted below. The referenced pages and lines correspond to the pages and lines of the “Revised Manuscript with Track Changes”.

Kind regards,

Shahram Oveisgharan, MD

REVIEWER 1

R1.1 My main concern is the clinical meaning of this study. What do the data tell us? Can we conclude anything for screening or caring for the elderly based on this data?

This is an important point. We hope that the revised discussion contextualizes the meaning of our findings with respect to the clinical care of older adults and directions for further aging research. The added paragraph (Page 20, lines 382-389) is included below:

“The differences observed with transition modeling between the temporal manifestations of mobility disability and parkinsonism were not merely descriptive but were associated with differences in their individual and joint associations with risk of death. These findings have important public health consequences with respect to risk stratification of older adults, emphasizing the importance of vigilance not only for incipient mobility disability, but also for the concurrence of parkinsonian signs. Moreover, the presence of both impairments as harbingers of an increased risk of death might be an important clinical indication for the necessity of more aggressive multi-modal lifestyle interventions and support to maintain survival in older adults.”

R1.2 I would suggest shortening the discussion which in large parts repeats the results and try to allude to these questions if not possible with the presented data give an outlook on how such analyses could help with this in the future.

We have shortened the discussion while adding additional analyses and responding to the concerns raised by the reviewer’s in their comments.

R1.3 Does the finding of the clearly increased risk to develop Parkinsonism after having developed mobility disability mean that slowing of gait is an under-recognized early sign of Parkinsonism?

The reviewer raised an important point. We found that more than 80% of older adults developed mobility disability, based on slowed gait speed, prior to death, a finding that is congruent with prior survey studies reporting mobility impairment to be the most common type of disability in late-life (29). In a previous study from the same cohort, we reported that isolated parkinsonian gait impairment was the most common isolated parkinsonian sign in older adults who went on to develop incident parkinsonism (20). However, as is mentioned by the reviewer 2 at R2.1, a slow gait is a motor phenotype that has a heterogenous group of risk factors including osteoarthritis and peripheral edema that are not risk factors for parkinsonism. In the current study, 60% of participants who developed mobility disability did not develop parkinsonism, a finding that suggests that in a large proportion of older adults mobility disability is not an early sign of parkinsonism. Gait speed may be slowed by numerous defects anywhere in the distributed motor control systems, which extend from the brain through the entire CNS to reach peripheral muscle. This may account in part for why gait speed is a robust, but non-specific early sign of diverse aging motor phenotypes and is not just an early sign of parkinsonism. As such, our data highlight a much more complex relationship between slowed gait speed and parkinsonism in older adults. This is added to the discussion (Pages 19-20, lines 367-381).

R1.4.A Table 1 is difficult to read, the legend does not state what is given outside and inside the brackets.

We hope the changes in Table 1 clarify what values are included within and outside the brackets.

R1.4.B Also table 1 could possibly give interesting clinical clues, Could the numbers on other diseases or symptoms give insights into risk factors for the two mobility impairments under study? or were there surprises as some expected risk factors did not show up here??? Why is that?

We thank the reviewer for this comment. In fact, Table 1 data does provide clues for possible risk factors for the two motor phenotypes. For example, we expected joint pain, a proxy for osteoarthritis, to be a risk factor for mobility disability. Table 1 data indicates that 30% of the no motor impairment group (NI) had joint pain at study baseline compared with 37% in the mobility disability (MD) group. Using the multistate modeling (S3 Table), we find that joint pain was a risk factor for mobility disability in the transition from no motor impairment (HR=1.34, 95% CI: 1.13 – 1.57, <0.001). Examining a possible risk factor for parkinsonism, we hypothesized that the number of vascular diseases might be a risk factor for parkinsonism based on our prior studies in which we found cerebrovascular brain pathologies explained more of the late-life parkinsonism progression compared with neurodegenerative brain pathologies (30). Table 1 data indicates that participants of the parkinsonism group (PARK) had more vascular diseases (mean=0.2, SD=0.4) compared with participants in the NI group (mean=0.1, SD=0.3). However, the multistate modeling did not find vascular diseases to be a risk factor for transition to parkinsonism (S2 Table). This may be due in part to the low frequency of vascular disease at study baseline.

Although the primary objectives of this study were examining relationship between the development of two motor phenotypes and their association with the risk of death, we updated the secondary analyses section of the results (Page 15, lines 265-273) and the supplementary file (S1 – S5 Tables) adding details about the association of the examined risk factors with the motor phenotypes and whether the study’s main findings were attenuated after further adjustment for these risk factors.

We agree with the reviewer that it is of great importance to identify risk factors associated with each of the two mobility impairments which we examined in this study. To adequately address this important issue, a larger study and a more comprehensive survey of potential risk factors is needed. This point has been added to the discussion. Considering that the primary objective of this manuscript was to examine the relationship between the development of two motor phenotypes and their association with the risk of death, we chose not to pursue this subject in the current study. We hope to address this important question more comprehensively in a future study (Page 22, lines 435-437).

The relevant changes in the revised manuscript are provided below:

Results (Page 15, lines 265-273):

“We examined whether controlling for chronic health conditions attenuated the associations of incident motor impairments and the risk of death (S1 – S3 Tables). Vascular risk factors were not associated with any of the 9 transitions. Vascular diseases increased the risk of death in participants who developed only mobility disability. Joint pain increased the risk of mobility disability in participants without any motor impairment. However, further adjustment for vascular diseases or joint pain did not change the inter-relationship of incident mobility disability and incident parkinsonism or their associations with the risk of death (S4 and S5 Tables).”

Discussion (Page 22, lines 435-437):

“To include additional phenotypes such as cognitive impairment or falls and to identify risk factors for transitions among these aging phenotypes a larger study would be necessary.”

REVIEWER 2

R2.1 I have some conceptual concerns about the authors employing these two “motor phenotypes.” “Mobility disability” has a clear-cut definition and indicates walking speed. This is a heterogeneous group, as walking speed is often impacted by musculoskeletal issues, peripheral edema and neuropathy, and other conditions that are common with aging. “Parkinsonism” as defined here, is based on UPDRS rating but does not comply with clinical criteria for Parkinson’s disease (bradykinesia plus one of the following- tremor, rigidity, characteristic gait changes) and was determined by trained nurses rather than a movement disorders specialist. It seems possible therefore that participants with other forms of gait disorders that share certain features with PD could be misclassified, and that having either tremor (also very non-specific at this age) or rigidity could then lead to classification as parkinsonism. I understand that the goal of the work was not to diagnose PD, but these distinctions impact how we think about the results in terms of mechanisms and guidance for screening methodologies. To illustrate this, one interpretation of the results is that “mobility disability” represents a prodromal stage of parkinsonism with similar underlying neurobiology, but another interpretation is that as slow gait progresses it can mimic parkinsonian gait. Potential suggestions to address these uncertainties would be a sensitivity analysis with “parkinsonism” defined as bradykinesia score > 2 and one other feature.

In this comment, the reviewer has concerns about both motor phenotypes examined in this study: mobility disability and parkinsonism.

A. Response to the concern about mobility disability:

1) We agree with the reviewer that walking speed is often impacted by musculoskeletal conditions. We examined available joint pain data as a proxy for musculoskeletal conditions. Joint pain at baseline was associated with a higher risk of incident mobility disability, but not with the risk of parkinsonism or death (S3 Table). Notably, adjustment for the joint pain did not change our primary findings about the inter-relationship of incident mobility disability and incident parkinsonism (S5 Table). These results have been added to the revised text and are included below (Results, Page 15, lines 265-273):

B. Response to the concern about parkinsonism:

1) We agree with the reviewer that the UPDRS, used for the assessment of parkinsonism, is not a quantitative instrument. Nonetheless, this instrument has been used for many years in diverse cohorts and predicts important adverse health outcomes (references 4, 17). As pointed out above (R1.3), the longitudinal findings in the current study extend prior cross-sectional reports and provide evidence suggesting that parkinsonism and mobility disability are related but distinct motor phenotypes (Discussion: Pages 19-20, lines 367-381).

2) We agree with the reviewer that the lack of assessment by a movement disorder specialist may lead to an underestimate of the prevalence of PD or atypical parkinsonism. This has been added as one of the study’s limitations (Discussion, Page 23, lines 449-453). However, we have used the term “parkinsonism” which may capture a much broader and diverse syndrome as has been done by others including well-known and well-respected movement disorder specialists (2,4).

3) Our study, like other community or population-based studies, does not use a movement disorder specialist, but relies on self-report or medical records for the diagnosis of PD and our studies employ nurse clinicians for the assessment of parkinsonism. In several previous publications, we have reported data showing that the UPDRS assessments by the nurse clinicians and the categorization of incident parkinsonism have high inter-rater reliability and short-term stability both among nurses and compared with a movement disorders specialist (Methods: Page 6, lines 111-115; References 17-18). Our prior postmortem studies of adults with parkinsonism indicate that late-life parkinsonism is a heterogeneous disorder that is most commonly related to cerebrovascular disease pathologies (>80%) while PD pathology was observed in a minority of cases (<10%). Moreover, older adults without a clinical diagnosis of PD but with postmortem evidence of PD pathology or adults with a clinical diagnosis of PD most commonly show mixed-brain pathologies (Reference 30). Thus, both the clinical prevalence of PD in the population and postmortem evidence of PD pathology is low.

4) Nonetheless, to highlight the robustness of our findings, we have added the suggested sensitivity analysis in which incident parkinsonism was defined as the presence of bradykinesia, a cardinal sign of PD, with one or more of the other three parkinsonian signs. Analysis using this new definition for incident parkinsonism did not change our main findings, which are summarized and added to the revised text (Results: Page 16, lines 297-303) and the supplementary material (S3 Fig, S7 Table).

The changes outlined above which have been added to the revised manuscript to address the reviewer’s concerns are provided below.

Methods (Page 6, lines 111-115)

“Nurse clinicians assessed parkinsonian gait, rigidity, bradykinesia, and tremor annually using 26 items from a modified motor section of the original United Parkinson’s Disease Rating Scale (UPDRS) (17). These measures have high inter-rater reliability and short-term stability among nurses and compared with a movement disorders specialist (18).”

Results (Page 16, lines 297-303):

“Of the four parkinsonian signs assessed in this study, bradykinesia is considered a cardinal sign for diagnosis of Parkinson disease. Therefore, to examine the robustness of findings, we repeated our analyses after redefining incident parkinsonism based on the presence of bradykinesia together with at least another parkinsonian sign (tremor, rigidity, parkinsonian gait). Our primary findings showing that mobility disability increases the risk of parkinsonism and that individuals with both mobility disability and parkinsonism have the highest risk of death were unchanged (S3 Fig, S7 Table).”

Discussion (Page 23, lines 449-453):

“While the assessments by nurse clinicians have high inter-rater reliability and short term stability both among nurses and compared to a movement disorders specialist, participants were not assessed by a movement disorders specialist, which might have led to an underestimate of the prevalence of PD or atypical parkinsonism in the current study (18,19).”

R2.2 Add information if available on whether any participants were diagnosed clinically with PD. One additional consideration worth mention in the discussion is that if participants were diagnosed clinically with PD, they may have been started on symptomatic medications that would impact their gait speed. If this information is available it would be helpful to include it.

We repeated our analyses after excluding 14 of 867 participants who had reported Parkinson’s disease during this study and our primary findings were unchanged. This sensitivity analysis is summarized in the revised text (Results: Page 16, lines 290-296) and added to the supplementary material (S2 Fig, S6 Table).

Results (Page 16, lines 290-296):

“Parkinsonism is a heterogeneous syndrome including older adults receiving different medications, diverse medical conditions and degenerative disorders including PD. To ensure that our findings were not affected by a subset of individuals with PD, we excluded individuals with a clinical diagnosis of PD (n=14) and repeated our analyses. Our primary findings were unchanged: mobility disability was a risk factor for incident parkinsonism and the highest risk of death was among participants with both mobility disability and parkinsonism (S2 Fig, S6 Table).”

R2.2-A Finally, it is very important to emphasize the participants with cognitive impairment were excluded. As the authors mention, cognition and gait are closely related, and thus the findings of this manuscript may not apply to the general population.

We agree and hope that the changes in the revised manuscript clarify that we excluded individuals with cognitive impairment at baseline from the current analyses. We updated the discussion (Page 22, lines 429-437) by highlighting the facts that examining the relationship between gait speed and cognition was reported in a previous study (Reference 10), and that our sample size for the current study limited our analyses to only 2 intermediate states (mobility disability and parkinsonism). We also have noted that this aspect of the current study design limits generalizing its findings to the general population which includes the full spectrum of late-life cognitive impairment (Discussion: Page 23, lines 447-449). The revisions are provided below:

Discussion (Page 22, lines 429-437):

“Since this modeling approach examined nine transitions and six states, there was not enough power to examine additional phenotypes. For example, adding an additional phenotype such as cognitive impairment would increase the number of states from 6 to 17 and the transitions from 9 to 31. Moreover, we have examined the relationship between incident cognitive impairment, mobility disability and death in the current cohort in a prior publication (10). We therefore excluded individuals with cognitive impairment at baseline to avoid confounding our results. To include additional phenotypes such as cognitive impairment or falls and to identify risk factors for transitions among these aging phenotypes, a larger study would be necessary.”

Discussion (Page 23, lines 447-449):

“Due to the number of transitions examined in the current study, we excluded participants with cognitive impairment that limits generalization of our study findings to the population with cognitive impairment.”

R2.2-B The authors should also state how cognitive impairment was defined, to clarify the potential cognitive range of participants that were excluded.

Details about the battery employed for cognitive testing and assessment of cognitive status as well as details about the number of participants excluded from the study because of cognitive impairment have been added to the revised text. These changes are provided below (Methods: Page 7, lines 132-139):

“The annual structured evaluation included administration of a battery of 17 cognitive tests. A neuropsychologist reviewed the cognitive tests’ results, and a physician with expertise in dementia reviewed annual findings including the summary of the neuropsychologist and classified the cognitive status of participants as no cognitive impairment, mild cognitive impairment, and dementia including probable and possible Alzheimer’s disease, according to established criteria (23). In this study, we excluded participants whose cognitive status at the baseline was mild cognitive impairment (n=895) or dementia (n=212), or the cognitive status could not get determined (n=33).”

REVIEWER 3

R3.1 Use of just gait speed for mobility disability may be one of the limitations of this study as previous studies have shown that longitudinal monitoring of postural sway may yield early detection of progressive motor decline.

The reviewer makes an important point which cannot be addressed in this analytic cohort as longitudinal measures of sway are not collected as part of the annual gait testing. This is noted as a limitation (Discussion: Page 23, lines 457-460), which is provided below:

“Mobility disability was defined by a slow gait speed, rather than using more granular mobility metrics including sway score not collected longitudinally in this cohort, that may be less sensitive in capturing early stages of mobility impairment.”

R3.2 Other risk factors that could contribute to balance control are specific vestibular deficits, somatosensory and visual deficits that should be taken in to account as risk factors for falls in elderly.

As discussed above in response to R3.1, R2.2-A, and R1.4.B, a much larger sample would be needed to examine these important risk factors and to include falls as an intermediate state together with incident parkinsonism and incident mobility disability and death. These details have been added to the revised text and is provided below (Discussion, Page 22, lines 429-437):

R3.3 Survival is less in atypical parkinsonian syndromes. Also falls, postural instability are more common in these patients. Where these patients diagnosed by a movement disorders specialist and were you able to further characterize the parkinsonian syndrome? In line with this comment, in line 205-207 you talk about risk of death association in participants who developed mobility disability first or parkinsonism first and that the risk was not different between the two group. Again it is interesting to examine what percentage of these patients had typical vs atypical parkinsonism.

We agree with the reviewer. As noted above in R2.1, study participants were not examined by a movement disorder specialist. Therefore, we do not have information about typical and atypical parkinsonism. This point is included as one of the study’s limitations (Discussion, Page 23, lines 449-453), which is provided below:

R3.4 You mentioned that you have excluded the patients who had cognitive impairment at baseline. Did you continue to evaluate cognitive function longitudinally? Previous studies have shown a relationship between worsening of balance and cognitive decline.

We agree with the reviewer. Please see our response to your prior comments R3.1 and R3.2, and to R2.2-A, and R1.4.B. In summary, we would need a much larger sample to examine incident cognitive or balance impairment in addition to the two motor phenotypes examined in the current analyses.

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PLoS One. doi: 10.1371/journal.pone.0246206.r003

Decision Letter 1

Stephen D Ginsberg

15 Jan 2021

Incident mobility disability, parkinsonism, and mortality in community-dwelling older adults.

PONE-D-20-20718R1

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PLoS One. doi: 10.1371/journal.pone.0246206.r004

Acceptance letter

Stephen D Ginsberg

19 Jan 2021

PONE-D-20-20718R1

Incident mobility disability, parkinsonism, and mortality in community-dwelling older adults.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Table. Association of vascular risk factors with mobility disability, parkinsonism, and death classified by the motor impairment status before the outcome.

(DOCX)

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S2 Table. Association of vascular diseases with mobility disability, parkinsonism, and death classified by the motor impairment status before the outcome.

(DOCX)

Click here for additional data file.^{(20.6KB, docx)}

S3 Table. Association of joint pain with mobility disability, parkinsonism, and death classified by the motor impairment status before the outcome.

(DOCX)

Click here for additional data file.^{(20.5KB, docx)}

S4 Table. Main findings of the study after further adjustment for vascular diseases.

(DOCX)

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S5 Table. Main findings of the study after further adjustment for joint pain.

(DOCX)

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S6 Table. Main findings of the study after exclusion of 14 participants who were diagnosed to have Parkinson disease during the study.

(DOCX)

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S7 Table. Main findings of the study after replacing parkinsonism with bradykinetic parkinsonism.

(DOCX)

Click here for additional data file.^{(20.9KB, docx)}

S1 Fig. States and transitions in a multi-state model of incident mobility disability and risk of death.

This figure describes a multi-state model of incident mobility disability and death. The boxes show the 3 possible states and the arrows show the 3 possible transitions.

(TIF)

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(TIF)

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S3 Fig. States and transitions in a multi-state model of incident mobility disability, incident bradykinetic parkinsonism, and risk of death.

This figure illustrates the frequencies of participants in each of the six states and nine transitions examined in a multi-state model of incident mobility disability, bradykinetic parkinsonism, and death. Mobility disability was defined as gait speed less than 0.55 m/s in an 8-feet walk test. Bradykinetic parkinsonism was defined as presence of bradykinesia and at least one other parkinsonian sign (which are rigidity, tremor, parkinsonian gait). All participants included in this study were initially without mobility disability or parkinsonism at the analytic baseline. During the course of this study, nine paths for transition were possible between the baseline state of no motor impairment, four intermediate states of varying degrees of motor impairment, and the final absorbing state of death.

(TIF)

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Data Availability Statement

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PERMALINK

Incident mobility disability, parkinsonism, and mortality in community-dwelling older adults

Shahram Oveisgharan

Lei Yu

David A Bennett

Aron S Buchman

Roles

Abstract

Background

Methods

Results

Conclusion

Introduction

Methods

Participants

Table 1. Baseline clinical characteristics based on final pattern of motor impairments developed during the study.

Assessment of motor impairment

Assessment of mobility disability

Assessment of parkinsonism

Assessment of other clinical variables

Statistical analyses

Fig 1. States and transitions in a multi-state model of incident mobility disability, incident parkinsonism, and risk of death.

Results

Incident mobility disability

Fig 2. Probability of developing mobility disability with and without prior parkinsonism.

Incident parkinsonism

Fig 3. Probability of developing parkinsonism in individuals with and without prior mobility disability.

Incident motor impairment and risk of death

Fig 4. Probability of death in older adults with and without prior motor impairments.

Secondary analyses

Discussion

Supporting information

Acknowledgments

Data Availability

Funding Statement

References

Decision Letter 0

Stephen D Ginsberg

Roles

Author response to Decision Letter 0

Decision Letter 1

Stephen D Ginsberg

Roles

Acceptance letter

Stephen D Ginsberg

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

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