Changes in Body Composition Before and After Parkinson’s Disease Diagnosis

Abstract

Background:

Weight loss is common in Parkinson’s disease (PD). However, little is known about when it starts, how PD changes as it progresses, and whether there is a differential loss of lean or fat mass. The objective of this study was to examine how body composition changes before and after PD diagnosis.

Methods:

In the Health, Aging, and Body Composition study (n = 3075; age range, 70–79 years), body composition was assessed using dual-energy x-ray absorptiometry on an annual or biennial basis from year 1 to year 10. For each PD case each year, we calculated the difference between their actual body composition measures and expected values had they not developed PD. Using linear mixed models with crossed random effects, we further examined the trend of change in body composition measures before and after PD diagnosis.

Results:

A total of 80 PD cases were identified in this cohort. Compared with their expected values, PD cases began to lose total and fat mass about 6–7 years before diagnosis, although the differences were not statistically significant until 3–5 years after diagnosis. The loss was substantial and persistent, with statistically significant trends of loss for total body mass (P = 0.008), fat mass (P = 0.001), and percentage fat (P < 0.001). In comparison, lean mass was stable throughout the follow-up (P = 0.16). Overall, 96% of the body mass loss in PD cases was from the loss of fat mass.

Conclusions:

In this longitudinal analysis with objective measures of body composition, we found persistent weight loss in PD cases, predominantly in fat mass, starting a few years before diagnosis.

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder that is clinically diagnosed by the presence of motor dysfunction such as bradykinesia, rigidity, tremor, and postural instability.¹ PD affects approximately 1 million individuals 65 years or older in the United States and is projected to increase by 25% by 2030 and thus presents an increasing burden on health care systems.² Sporadic PD often takes decades to develop and is typically diagnosed when its cardinal motor signs become clinically evident late in life. In the past 2 decades, we have learned that a wide range of nonmotor symptoms may develop many years before PD diagnosis. A thorough understanding of these nonmotor symptoms may be critical to early disease recognition and a better understanding of disease development. To date, the best-studied nonmotor symptoms are olfaction loss, rapid eye movement sleep behavior disorder, depression, cognitive changes, and constipation.³ In comparison, other symptoms have received less attention.

Weight loss is common in PD patients^4–8 and is often associated with severe motor dysfunction, higher comorbidity, poor physical and mental function, frailty, and increased mortality.^6,9–13 Interestingly, 2 recent prospective studies reported that lower body mass index was associated with a higher risk of PD, suggesting that weight loss may start before PD diagnosis.^14,15 To the best of our knowledge, only 1 previous population-based study has used repeatedly obtained body weights to assess when and how body weight changes before and after PD diagnosis. In the Health Professionals Follow-up Study, Chen et al reported that PD cases tend to begin weight loss 2–4 years before PD diagnosis, and the trend persisted after PD diagnosis. On average, compared with individuals who did not have PD, cases lost 3.86 kg more body weight throughout the follow-up.⁵ However, this study used self-reported body weight and did not differentiate the loss of lean versus fat mass, which by itself may have implications for the health and survival of older adults. We therefore used objective measures of body composition, including total, lean, and fat mass, repeatedly assessed in a community-based biracial cohort to examine changes in body composition in PD cases up to a decade before and after PD diagnosis.

Materials and Methods

Study Design and Study Population

The Health, Aging and Body Composition (Health ABC) study was designed to study risk factors for functional decline in older adults, especially changes in body composition, behavioral and physiological conditions in the context of aging.¹⁶ Details of the study were published previously.¹⁶ Briefly, the study recruited 3075 well-functioning older adults (aged 70–79 years; 51.4% women; 41.6% blacks) in 1997–1998 living in Pittsburgh, Pennsylvania, and Memphis, Tennessee. Inclusion criteria included (1) no reported difficulty in walking a quarter mile or climbing up 10 steps, (2) no mobility-related difficulty in performing everyday tasks, and (3) no intention to move out of the study area in the next 3 years. Exclusion criteria included (1) active cancer treatment in the past 3 years, and (2) current participation in a lifestyle intervention trial. Participants enrolled in the study by completing the year 1 baseline clinic visit from April 1997 to June 1998. Their health and survival were monitored for up to 17 years with annual or biennial clinic visits, semiannual/quarterly phone calls, and hospitalization and death surveillance. Body composition was measured using dual-energy x-ray absorptiometry (DXA) at clinic visits on an annual basis from year 1 to year 6, then biennially from year 6 to year 10, and then again year 16. In this study, we excluded data from the 16th year because of the long gap between years 10 and 16, and few PD cases were alive and participated in the year 16 clinic visit. The body composition of eligible participants was analyzed from baseline until the date of death, last contact, or year 10 clinic visit, whichever came first, with an average of 7.8 years. All participants provided written informed consent, and the study protocol was approved by the institutional review boards (IRBs) at the University of Pittsburgh and University of Tennessee – Memphis. This specific secondary data analysis was IRB-exempted as nonhuman research by the Michigan State University.

Measurements

Body Composition

Body weight or total body mass, lean mass, and fat mass were acquired from total body scans using fan-beam dual-energy x-ray absorptiometry (Hologic QDR 4500A, version 8.20a; Hologic, Waltham, MA). The percentage of fat mass was calculated by dividing the total fat mass by the total body mass. The validity and reproducibility of this DXA approach have been previously reported,^17,18 and its performance in the study was further assured by daily and cross-calibration phantoms at both study sites,¹⁹ and DXA data were calibrated accordingly for all years.²⁰ Identical scan protocols were used for all participants from both sites.

PD Ascertainment

In 2015, we conducted a retrospective PD case adjudication by comprehensively reviewing relevant medical data collected during follow-up visits, which we reported in detail previously.²¹ Briefly, we first identified a total of 156 potential PD cases for whom any of the following is true: (1) use of antiparkinsonian medications (carbidopa/levodopa, dopamine agonists, monoamine oxidase B inhibitors, amantadine, or anticholinergic drugs) at any available clinic visit; (2) self-reported PD diagnosis; (3) adjudication of PD as the cause of hospitalization; (4) PD as the adjudicated cause of death. For each potential case, 2 experienced movement disorder specialists independently reviewed relevant data over the entire follow-up, accounting for the number of independent sources that indicated a PD diagnosis, internal consistency within each source, and evidence against PD diagnosis. The final diagnostic adjudications were made by consensus. Of the 156 potential cases identified, 81 were confirmed as having PD. Of the rest, 58 had an uncertain determination and thus were excluded from the analysis; the other 17 were adjudicated as no PD cases and thus were retained in the study as controls. We further defined the year of diagnosis as the first year that PD medication or diagnosis was reported. If PD was first identified by hospitalization or death, we defined the year of diagnosis as the midpoint of first identification and the previous year of the medical survey without reports of PD medication use.

Year From PD Diagnosis

In the analysis, we used the year of PD diagnosis as the reference time. For each PD case at each measurement, we calculated the number of years in reference to the time of PD diagnosis by subtracting the calendar year of PD diagnosis from the year of measurement. For example, if a case got PD diagnosis in 2003 and had body composition measured 5 times, in 1999, 2001, 2003, 2006, and 2008, the corresponding time in reference to PD diagnosis will be 4 and 2 years before, the year of, and 3 and 5 years after PD diagnosis.

Covariates

We considered the following covariates in this study — age, sex, race, clinic visit year, study site, standing height, and brisk walking. Age and brisk walking were specific to each clinic visit. Sex, race, and study site were reported at baseline. Race is white or black, and study site is Memphis or Pittsburgh. Clinic visit year represents the number of years starting from baseline, which has values from 1 to 10 representing the 1st (baseline) to the 10th year of clinic visits. Body height was measured to the nearest 0.1 cm using a wall-mounted stadiometer at the clinic visit in years 1, 4, 6, 8, and 10. At these visits, standing height measurements were taken up to 4 times. The final body height was determined as the following: (1) the average if 2–3 measurements were obtained, (2) the average of the last 2 measurements if all 4 measurements were made, or (3) the single measurement if only 1 messurement was taken. For study visits at which height was not measured, we used measurements from the most recent previous visit. Brisk walking was assessed annually as the self-reported average time spent per week walking briskly and was defined dichotomously in the analysis as 90 minutes or more per week.

Statistical Analysis

The current analyses were limited to participants with valid data on body composition: 80 PD cases with fat and lean mass and 77 with total body mass and percentage of fat mass. The number of non-PD participants in the analyses also varied by the dependent variables, ranging from 2917 to 2830. To examine how body composition changed in PD cases before and after the diagnosis, we used a statistical approach similar to what we published previously.⁵ Briefly, in each clinic visit year, among non-PD participants, we first fitted a linear regression model of each body composition measure on age, sex, race, study site, height, and brisk walking and obtained the beta coefficients. We then applied these coefficients to PD cases and calculated their expected body composition measures had they not developed PD (hereafter referred to as expected measures). We finally calculated residuals, which, by definition, represent the difference between their actual body composition measures and the expected values in that particular calendar year had they not developed PD. After con-ducting this analysis for each clinic visit at which body composition was measured, we compiled all available residuals for PD cases and realigned the time scale using the year of PD diagnosis as reference. We subsequently conducted a mixed model with crossed random effects²² to examine trends of the residuals from the previous step across all years in reference to PD diagnosis. Specifically, in addition to the main model with residuals on the linear and quadratic terms of the time, we accounted for potential correlations between multiple measures within each PD case and between expected body composition measures from each clinic visit by examining crossed random effects for participants, by-participant slope on time, and the year of clinic visit. In the current analyses, we excluded participants with missing values in body composition measures and brisk walking, assuming missing at random. The missing values in height were imputed from the nearest previous visit. There was no missing value on all other covariates after the above exclusion and imputation. The linear regressions for measures at each clinic visit were conducted with SAS version 9.4 (SAS Systems Inc., Cary, NC), and the mixed model with crossed random effects was conducted with Stata version 16.0 (StataCorp, College Station, TX). A P < 0.05 was considered statistically significant.

Results

Baseline Characteristics

We present the baseline population characteristics of participants who had developed (cases) and had not developed (non-PD participants) PD during the follow-up in Table 1. For simplicity, we used cases and non-PD participants to refer to these 2 groups. Because of the narrow age range of our study population, there was no significant age difference between PD cases and non-PD participants (74.0 2.8 vs 73.6 2.9 years, P = 0.17). Compared with non-PD participants, PD cases were more likely to be male (60.0% vs 48.1%, P = 0.04) and white (75.0% vs 58.0%, P < 0.01). The body composition, standing height, and brisk-walking measures did not significantly differ between PD cases and non-PD participants at baseline.

TABLE 1.

Baseline participant characteristics of Parkinson’s disease (PD) cases and non-PD participants

	PD cases (n = 80)	Non-PD participants (n = 2917)	P
Continuous variables, mean (SD)
Age (y)	74.0 (2.8)	73.6 (2.9)	0.17
Standing height (cm)	168.1 (9.1)	166.2 (9.4)	0.07
Total body mass (kg)	75.9 (12.4)	75.5 (14.9)	0.62
Total body lean mass (kg)	48.4 (9.1)	46.6 (10.0)	0.07
Total body fat mass (kg)	25.6 (7.1)	26.8 (8.8)	0.21
Percentage of fat mass (%)	33.5 (7.0)	35.0 (7.8)	0.06
Categorical variables, n (%)
Sex			0.04
Female	32 (40.0)	1515 (51.9)
Male	48 (60.0)	1402 (48.1)
Race			< 0.01
White	60 (75.0)	1691 (58.0)
Black	20 (25.0)	1226 (42.0)
Brisk walking			0.71
≥90 minutes per week	8 (10.0)	331 (11.35)
<90 minutes per week	72 (90.0)	2586 (88.65)
Site			0.76
Memphis	39 (48.75)	1472 (50.5)
Pittsburgh	41 (51.25)	1445 (49.5)

Because of missing data, the exact sample sizes of cases/non-PD participants were 77/2830 for total body mass and body fat percentage. P values were based on the Mann–Whitney U test and the chi-square test for continuous and categorical variables, respectively.

Trend Analysis

Figure 1 shows the results from the analysis using mixed models with crossed random effects. The horizontal reference line 0 represents the expected changes in body composition measures of non-PD participants because at any given point the mean of their residuals should be 0. Therefore, this line also represents the expected changes in body composition of PD cases had they not developed PD. In this analysis, all body composition measures of PD cases were comparable to their expected values before PD diagnosis; however, total body mass, fat mass, and percentage of fat mass began to decrease a few years before PD diagnosis, which persisted through all periods after PD diagnosis. For total body mass, fat mass, and percentage of fat mass, the modeling suggests a curvilinear relationship to the time to PD diagnosis with a monotonic trend of loss starting about 6–7 years prior to diagnosis (P values for testing quadratic time terms were 0.008, <0.001, and <0.001, respectively; Table 2). By years 5, 3, and 1 after diagnosis, total body mass, fat mass, and percentage of fat mass, respectively, became statistically different from their expected values and the decreasing trend persisted (Supplemental Table S1). Nine years after diagnosis, the average cumulative loss was 5.7 kg for total mass and 5.5 kg for fat mass. In comparison, the total lean mass of PD cases was stable over the entire observational period (Table 2) with an overall gain of 0.38 kg (Supplemental Table S1).

FIG. 1.

Mean changes in various body composition measures of PD cases relative to their expected values had those cases not developed PD before and after diagnosis. (A–D) Adjusted predictions with 95% confidence intervals for the mean change in (A) total body mass, (B) total body lean mass, (C) total body fat mass, and (D) percentage of fat mass.

TABLE 2.

Estimates of the linear mixed model for the time trend of changes in relative body composition measures of Parkinson’s disease (PD) cases compared with their expected values had they not had PD

	Linear time		Quadratic time
Body composition measures	Estimate (SE)	95% CI	Estimate (SE)	95% CI
Total mass (kg)	−0.3 (0.1)a	(−0.5 to −0.1)	−0.03 (0.01)a	(−0.04 to −0.007)
Total lean mass (kg)	0.007 (0.04)	(−0.008 to 0.09)	−0.006 (0.004)	(−0.01 to 0.002)
Total fat mass (kg)	−0.3 (0.07)a	(−0.5 to −0.2)	−0.02 (0.007)a	(−0.04 to −0.01)
Percentage of fat mass (%)	−0.3 (0.06)a	(−0.4 to −0.2)	−0.02 (0.006)a	(−0.03 to −0.01)

CI, confidence interval.

Time refers to years from PD diagnosis, which was included as a linear term and a quadratic term. Estimate is the fixed effects of time on the difference between actual body composition of PD cases and their expected body composition had they not had PD. Crossed random effects included random intercepts for clinical visit year and for participants, and by-participant random slope on time.

^aP < 0.01.

Discussion

In this longitudinal study with repeated measures of body composition, we found that the body weight of PD cases began to decrease a few years before diagnosis, which persisted into the years after diagnosis. By year 9 after PD diagnosis, the cumulative loss was on average about 5.7 kg. We further found that, on average, 96% of the loss was from loss of fat mass, whereas the lean mass in PD cases was well preserved.

Substantial evidence from case–control and cross-sectional studies have shown that PD patients had lower body weight and body mass index than controls.^{4,6,8,12,23–27} Some studies further reported that PD patients lose more weight after diagnosis than individuals without PD. The first report was published in 1976 and found a significant loss of body weight in 7 levodopa-treated PD patients compared with healthy controls, with an average loss of 6.28 kg over 1–3 years.²⁸ In 1995, Beyer et al⁴ reported that PD patients were 4 times more likely to report a significant weight loss of >10 pounds since disease diagnosis. Two later longitudinal studies reported PD patients lost an average of 1.8 kg weight over 1 year⁸ and 4.1 kg over 6.3 years of follow-up.⁶ Although the clinical and epidemiological data on weight loss in PD is substantial, they are not entirely consistent. Several studies have reported stable or even weight gain in PD patients. For example, Toth et al reported that the DXA measured total body mass was not significantly different between 16 PD patients and 46 controls.²⁹ Wills et al found that stable body weight was common in relatively young PD patients who participated in a PD clinical trial.⁹ Two other studies with small sample sizes also reported a stable weight among PD patients over 1–3 years of follow-up.^30,31 This inconsistency across studies may in part be explained by differences in study design, patient characteristics, sample size, length of follow-up, treatment strategies used for patients, and lack of repeated objective assessments of body weight.

Several studies further suggest that body weight in PD patients may begin to decline before disease diagnosis. In the Health Professionals Follow-up Study (HPFS) and the Nurse’s Health Study (NHS), Chen et al analyzed body weight reported every 2 years by 468 PD patients who were compared with participants without PD using similar methods as in this study. They found that PD patients began to lose weight 2–4 years before PD diagnosis despite accompanying increased energy intake⁵ and decreased physical activities.³² These trends persisted after diagnosis. To the best of our knowledge, this is the only longitudinal study in which the body weight of PD patients was repeatedly assessed before disease diagnosis. The finding is supported by another small clinical study of 49 PD patients with body weight before disease diagnosis abstracted from medical records. The authors reported PD patients had a mean weight loss of 1.19% in an average period of 2.4 years before the time of PD diagnosis.⁷ Therefore, the existing evidence, although limited, suggests that weight loss in PD patients may start in the prodromal stage.

Compared with previous studies, the current study has several notable strengths. Like the HPFS and NHS, the Health ABC study repeatedly measured the body weight of PD cases up to about a decade before and after the diagnosis. Beyond HPFS and NHS, body weight in Health ABC was not self-reported but more accurately assessed using DXA assays along with measures of body fat and lean mass, allowing analyses to examine differential changes in body composition compartments. Our study confirmed that persistent weight loss in PD cases likely starts a few years before PD clinical diagnosis. Thus, this is not affected by the use of any antiparkinsonian medications and may even occur before the presence of clinically evident motor symptoms, suggesting weight loss may be intrinsic to the natural history of PD starting from its prodromal stage. We further found that the loss was almost entirely because of the loss of fat mass. This observation of preferential loss of fat mass in PD cases is supported by some but not all the earlier small clinical studies. For example, in 1 study, 19 of 26 PD cases lose weight over a year, which was mainly because of loss of fat mass as measured by DXA.⁸ In contrast, another study of 58 PD cases reported a gain in average body weight and fat mass over 3 years measured by bioelectrical impedance analysis.³⁰ Compared with this existing literature, our study is population based, had a longer follow-up, and repeatedly assessed body composition using DXA, and our finding of a persistent loss of fat mass in PD cases was robust.

Although the exact reasons for weight loss in PD are yet to be identified, it may relate to the complex symptoms and signs that develop as PD pathogenesis progresses. For example, in the prodromal stage of PD, poor olfaction may adversely affect diet and nutrition,³³ which in turn gradually lead to changes in body composition. In support of this, Purdy et al reported that poor olfaction was associated with faster weight loss in older adults.³⁴ Experiments in transgenic mice have also shown poor olfaction to trigger a metabolic response that leads to increased catabolic energy utilization and a subsequent loss of body weight.³⁵ As PD progresses, its motor signs and complications such as tremor,³⁶ muscle rigidity,^36,37 and levodopa-induced dyskinesias³⁸ may further lead to increased energy expenditure and thus weight loss. Throughout the course of PD, these may further be complicated by other PD symptoms and signs such as depression,³⁹ constipation,⁴⁰ gastrointestinal disorders,⁴⁰ cognitive impairment,^11,41 dysphagia,⁴² and adverse events of dopaminergic treatment,^41,43 all of which may lead to a progressive and persistent weight loss in PD patients. The preferential loss of fat mass in PD is also intriguing and may relate to accelerated biological aging,^44,45 which is associated with the reduction of subcutaneous fat and the deposition of fat in nonadipose tissue in late adulthood by reducing adipogenesis through age-related activation of cellular stress response pathways and increased preadipocyte cytokine generation.^46,47 Further investigations are warranted to investigate the causes of weight loss and preferential loss of fat mass in PD patients.

This persistent weight loss in PD patients noted above should not be neglected, as it may have important adverse health consequences. In PD patients, weight loss is often associated with higher Hoehn & Yahr stage,¹⁰ higher score on the Unified Parkinson’s Disease Rating Scale,⁹ the lower density of nigrostriatal dopaminergic neurons,⁴⁸ lower cognitive function,^10–12 declined quality of life,¹⁰ a higher number of comorbidities,¹⁰ and increased risk of dependence and mortality.⁶ Moreover, the reduction of fat mass and the subsequent redistribution of adipocytes into muscle tissues may result in a higher risk of reduced muscle function and the development of frailty in PD patients. In support of this possibility, several studies reported lower fat mass was associated with more severe motor impairment in PD patients.^23,49 Further, 1 recent study found that PD patients had higher MRI-measured fat content in the bilateral psoas and thigh muscles than their age- and sex-matched healthy controls, which was associated with disease severity and frailty.¹³ Therefore, changes in weight and body composition in PD patients may inform disease progression and prognosis, offering an opportunity to improve the health and survival of PD patients.

The present study has several limitations. First, although our study identified 80 PD cases, their diagnosis was at different times of the follow-up. Therefore, the actual sample sizes were relatively small and varied at each specific time in reference to PD clinical diagnosis. Nevertheless, our study revealed persistent weight loss in PD cases that was highly statistically significant. Second, because of the small sample size at each time and the lack of systematic collection on data of antiparkinsonian treatments, we were unable to evaluate how PD treatments may affect body composition in the clinical course of PD. Third, the Health ABC study participants were old at enrollment (range, 70–79 years). Because of body composition changes as part of the aging process, our findings may not be readily generalizable to younger PD patients. Fourth, both PD diagnostic adjudication and time of diagnosis were retrospectively adjudicated based on cohort data collection, and thus inadvertent errors are likely. However, our findings of persistent weight loss and when it starts are relatively consistent with those of HPFS and NHS, which prospectively adjudicated PD diagnosis and further conducted rigorous medical record reviews by gathering diagnostic information from study participants and their treating physicians.^5,32 Fifth, we were unable to account for energy intake and expenditure in our analyses because such information is often difficult to capture in large populations of older adults. Finally, as in any longitudinal studies of older adults over an extended period, substantial loss to follow-up is inevitable. We were unable to account for this in our analysis in part because we realigned the data in reference to the time of PD diagnosis. It is possible that cases who only had a short follow-up were more likely to have an aggressive clinical course and more weight loss. If this is the case, we might have underestimated the extent of weight loss in PD.

In summary, in this longitudinal cohort of older adults with objective and repeated measurement of body composition, we found persistent weight loss in PD cases starting a few years before the diagnosis, which was predominantly loss of fat mass. Future studies are needed to understand the underlying mechanisms of this change in the body composition of PD patients and its potential impacts on disease progression and survival.