Predictors of Working Capacity Changes Related to Huntington’s Disease: A Longitudinal Study

Abstract

Background:

Huntington’s disease (HD) is an inherited neurodegenerative disorder that is characterized by motor, cognitive, and psychiatric symptoms. Although 65%of HD expanded gene carriers report changes in employment as the first functional loss, little is known about the predictors leading to changes of working capacity. Given the impact on quality of life, understanding of these factors is of great clinical value.

Objective:

This study evaluates disease specific characteristics and their predictive value in loss of working capacity in HD.

Methods:

Longitudinal data was collected through the worldwide observational study (Enroll-HD), with 15,301 participants in total and 2,791 HD and healthy control participants meeting the inclusion criteria. Changes in working capacity were analyzed by means of a survival analysis. Predictive values of demographic factors and clinical characteristics were assessed for premanifest and manifest HD through Cox regressions.

Results:

HD expanded gene carriers, manifest and premanifest combined, had a 31%chance of experiencing changes in employment after three years, compared to 4%in healthy controls. Apathy was found to be the most crucial determinant of working capacity changes in premanifest HD, while executive and motor dysfunction play an important role in manifest HD.

Conclusion:

HD expanded gene carriers are more likely to lose working capacity compared to healthy controls. Disease progression, altered motor function, cognitive decline, and in an early stage of the disease apathetic symptoms are indicative of negative changes in working capacity. Clinicians should recognize that early disease related changes, especially apathy, can affect working capacity.

Keywords

Huntington’s disease employment occupation survival analysis work status

Huntington’s disease (HD) is a hereditary neurodegenerative disorder, caused by an expansion of the cytosine-adenine-guanine repeat (CAG-repeat) on chromosome 4 [1]. The disease affects psychological well-being, cognitive performance, and motor function, therefore extensively impacting the quality of life [2 –4]. The mean age at disease onset is between 30 and 50 years [3]. The clinical diagnosis is generally reached when patients show indisputable motor signs [5, 6]. Motor signs include chorea, hypokinesia, dystonia, gait and oculomotor abnormalities. Nevertheless, cognitive dysfunctions such as decreased psychomotor performance, executive dysfunction, and lower attentional capacities are reported to occur 15 years prior to motor symptoms [5, 7]. Hence, most HD expanded gene carriers are employed whilst experiencing the first symptoms of the disease. Shifts in employment status, such as altered working hours, altered working conditions or a loss of gainful employment altogether are one of the earliest and most common changes in functional capacities, being reported by 65%of HD expanded gene carriers [8]. One of the risks, however, is that employers might misinterpret early clinical characteristics as deviant or unprofessional behavior [9]. As a consequence, forced loss of employment has a big impact on patient’s quality of life, psychological well-being and evidently their financial situation [10]. Studies focusing on employment in HD are limited. One such study, pertaining to employment changes in HD patients with minimal clinical symptoms (i.e., premanifest HD expanded gene carriers), found that a higher CAG-repeat length, lower global cognition and evident motor symptoms increased the chance of experiencing workplace disability. In addition, anxiety and depression were found to have an impairing effect on employment, whereas good mental and physical health were found to have a protective effect on work related problems [11]. Another study confirmed the previous finding that motor signs play an important role in deciding to stop working [9]. Additionally, the authors identified cognitive dysfunction, as measured by the Stroop color naming test, to contribute equally to the decision to leave work [9]. A study—aimed to determine which features of HD predict unemployment—found executive dysfunction and apathy to be the best determinants [12]. A limitation of these studies was the cross-sectional design, which is not very informative as a change of employment status is a process over time. These studies all aimed to assign HD symptoms to differences in employment status, however, the outcomes are divergent and taken together encompass almost every HD related symptom. Therefore, the aim of this longitudinal study is to examine if the rate of changes in working capacity in HD patients differs from healthy controls, and if so, to which disease specific characteristics these changes are related over time. This might result in a basis on which clinicians can further advise HD expanded gene carriers and their families.

METHODS

This study used the fourth periodic dataset, re-leased October 2018, of the worldwide longitudinal Enroll-HD study [13]. Enroll-HD is a global clinical research platform designed to facilitate clinical research in HD. Core datasets are collected annually from all participants as part of this multi-center longitudinal observational study. Data are monitored for quality and accuracy using a risk-based monitoring approach. All sites are required to obtain and maintain local ethical approval. In Enroll-HD, standardized data on nearly 19,000 participants is collected annually, which provides a vast but comprehensive database on HD [14]. Next to extensive demographical data, the database provides clinical information on participants’ cognitive, motor and psychiatric status. The current study included HD expanded gene carriers and healthy controls (e.g., participants not at risk for HD or family controls), who were between the ages of 20 and 65 years to ensure that they were at an age that they could potentially work and had a normal working capacity at baseline as defined by the Unified Huntington’s Disease Rating Scale Total Functioning Capacity (UHDRS-TFC), which is described later in this section. Of the 6,995 participants remaining, 4,204 did not yet have any follow-up measurements and were therefore excluded. This resulted in a final sample of 2,791 participants with a minimum of 1 year follow up (Fig. 1). The sample consisted of 1,542 HD expanded gene carriers and 1,249 healthy controls (Table 1).

Fig. 1

Flowchart of the original dataset and sample size for the longitudinal analysis of occupational functioning in HD.

Table 1

Comparison of demographics and clinical characteristics of HD expanded gene carriers and healthy controls with normal working capacity at baseline

	HD expanded gene carriers (n = 1,542)		Healthy controls (n = 1,249)		p
Demographics
Age^a	40.3	(10.8)	44.5	(11.7)	< 0.001
Sex f/m (%f)^b	898/644	(58.2)	782/467	(62.6)	0.020
Level of education^c	4	(3 –5)	4	(3 –5)	0.339
CAG-repeat^a	42.8	(2.8)	20.0	(3.4)	< 0.001
Clinical characteristics					-
UHDRS-TMS	6.3	(9.1)	1.2	(2.3)	< 0.001
SDMT^a	47.6	(13.6)	52.4	(10.8)	< 0.001
SCNT^a	69.8	(16.2)	76.2	(13.6)	< 0.001
SWRT^a	90.3	(19.1)	97.2	(16.3)	< 0.001
SIT^a	41.7	(11.8)	44.1	(10.6)	< 0.001
TMT-A^a	30.3	(16.4)	25.6	(10.1)	< 0.001
TMT-B^a	67.5	(44.9)	53.6	(26.9)	< 0.001
Apathy^c	0	(0 –0)	0	(0 –0)	< 0.001
Anxiety^c	5	(2 –7)	4	(2 –7)	0.188
Depression^c	3	(1 –5)	2	(1 –5)	0.019

HD, Huntington disease; UHDRS-TMS, Unified Huntington Disease Rating Scale-Total Motor Score; SDMT, Symbol Digits Modalities Test; SCNT: Stroop Color Naming Test; SWRT, Stroop Word Reading Test; SIT, Stroop Interference Test; TMT-A, Trail Making Test-A; TMT-B, Trail Making Test-B. ^aComparison by means of an independent sample t-test, the mean and standard deviation are reported. ^bComparison by means of a chi-squared test, the number of female and male participants are reported. ^cComparison by means of a Mann-Whitney U test, the median and interquartile range are reported.

Healthy controls had a CAG-repeat of ≤35 and HD expanded gene carriers had a CAG-repeat of ≥36. Furthermore, HD expanded gene carriers had to have a CAG-repeat length of ≤60 repeats in order to exclude participants who could qualify as having onset before the age of 20 years. Finally, CAG-repeat length, age, sex, and education level were reported as covariates. Participants were subjected to the core cognitive battery of Enroll-HD which consists of three cognitive measures, viz.: a) The Symbol Digits Modalities test (SDMT) is a test that requires the decoding of symbols, more correct responses indicate higher psychomotor speed [15]; b) The Stroop test consists of three cards, which requires participants to correctly name colors; the Stroop Color Naming Test (SCNT), read the names of colors; the Stroop word reading test (SWRT) and name the color of the ink instead of the name of the color that is printed;the Stroop interference test (SIT) [16]. Higher scores on the Stroop test indicate faster processing speed and better inhibitory performance; and c) The Trail Making Test part A and B (TMT-A and TMT-B) measures psychomotor speed and switching ability. Participants are asked to draw a line between ascending numbers (TMT-A) and to draw a line alternating between ascending numbers and letters (TMT-B). The time to finish is recorded. Lower scores indicate higher psychomotor speed and a better ability to switch attention [17]. Motor function was tested with the Unified Huntington’s Disease Rating Scale Total Motor Score (UHDRS-TMS), which measures common expressions of HD such as oculomotor function, bradykinesia, chorea, dystonia, gait and balance [18]. Higher UHDRS-TMS reflects increased motor dysfunction. Furthermore, physicians provide a diagnostic confidence level (DCL 0 –4) determining whether the assessed motor symptoms are unequivocal signs of HD (DCL = 4). Psychiatric symptoms were assessed using the Hospital Anxiety and Depression Scale (HADS) (range 0 –21) and the apathy score of the Psychiatric Behavioral Assessment short version (PBA-s) (range 0–16). These were chosen because of their predictive value in previous research pertaining to employment in HD [11, 12]. Higher scores indicate increased feelings of anxiety, depression and apathy [19, 20]. Change in working capacity was reported using the UHDRS-TFC, which is a physician-completed global measure of a patient’s functional abilities (range 0–13) [18]. Lower scores indicate worse functioning. The first item of the UHDRS-TFC reports whether a participant has the potential to work or is actually working (range 0–3). Scores are respectively ‘unable to work’, ‘marginal work only’ (e.g., volunteer), ‘reduced capacity for usual job’ (e.g., reduced hours or responsibilities) and ‘normal working capacity’.

Statistical analyses

R 3.5.3 [21] the survival v2.43-3 [22], MASS v7.3-51.4 [23], and icenreg v2.0.10 [24] packages were used for statistical analyses. The aim of this longitudinal study is to examine if the rate of changes in working capacity in HD differs from healthy controls, and to which disease specific characteristics these changes are related over time. Group differences between HD expanded gene carriers and healthy controls, and between HD expanded gene carriers with and without (partial) working capacity change, were analyzed using χ², independent sample t, and Mann-Whitney U tests according to parametricity of the variables. We selected all participants who had a normal working capacity at baseline and a minimum of 1 follow up visit. The maximum follow-up period was 3 years with a range of 3 months prior to and 7 months following the actual visit. A reduction in working capacity was determined at the next follow-up visit. Therefore, the exact date of change is not reported, resulting in so-called “interval censored” data. To take this type of data into account, we used the non-parametric Turnbull estimator for interval censored data instead of the usual Kaplan-Meier estimator (Fig. 2). Next, we subclassified the participants according to clinical manifestation of the disease. The UHDRS-TMS was used to determine premanifest (UHDRS-TMS < 5) or manifest (UHDRS-TMS ≥5) status of the participant. Subsequently, we used univariate and multivariate Cox models assessing the effect on the amount of years to loss of normal work status of the following variables (measured at baseline): age, sex, level of education, CAG-repeat length, UHDRS-TMS, SDMT, SCNT, SWRT, SIT, TMT-A, TMT-B, PBA-s apathy, and HADS anxiety and depression scale. For both the univariate and multivariate cox regression, the hazard ratio (HR) with a 95%confidence interval is reported.

Fig. 2

Survival curves depicting changes in working capacity of HD expanded gene carriers and healthy controls.

RESULTS

HD and healthy control-groups differed on all demographics and clinical characteristics, except for level of education and anxiety scores measured by the HADS (Table 1). Of the 2,791 participants working at normal capacity at baseline, a total of 2,418 participants retained normal working capacity over 3 years time, 273 were working with reduced capacity, 51 participants were working only marginally and 49 participants lost all working capacity. By use of survival curves we found a difference in the probability of changes in working capacity between HD and healthy controls after three years (Fig. 2). These survival curves provide an estimation of the changing probability over time that a person experiences a change in work. HD expanded gene carriers had an estimated 31%probability of a change in working capacity in three years’ time, whereas the probability of healthy controls was 4%.

Focusing on the data from which these estimates are derived, 22%(350 participants) of the 1,542 HD expanded gene carriers actually experienced a change in working capacity in 3 years’ time, compared to 1.8%(23 participants) of the 1,249 healthy controls. Of these 350 HD expanded gene carriers, 191 had received a diagnostic confidence level (DCL) of 4 (> 99%certainty affected) at baseline. HD expanded gene carriers who had a decrease of working hours/tasks or became incapable of working, differed on all variables from the HD-group without employment changes. Both groups consist of slightly more women. However, the ratio male to female was statistically equal (Table 2). After subclassification of the HD expanded gene carriers into a premanifest and manifest group, the univariate cox regressions for the manifest group showed that all demographic factors as well as clinical characteristics were significantly associated with changes in working capacity, except for sex (HR = 1.04, 95%confidence interval [CI] = 0.82–1.32, p = 0.760), education level (HR = 0.92, 95%CI = 0.83–1.02, p = 0.120), and anxiety levels (HR = 1.03 95%CI = 1.00–1.06, p = 0.082). Univariate cox regressions for the premanifest group also showed significant associations for all variables, except for sex (HR = 0.90, 95%CI = 0.57–1.42, p = 0.650), and education level (HR = 0.89, 95%CI = 0.74–1.08, p = 0.240).

Table 2

Comparison of demographics and clinical characteristics measured at baseline of HD expanded gene carriers with and without change in working capacity in the following 3 years

	Stable working capacity (n = 1,192)		Change in working capacity (n = 350)		p	Δ ^e
Demographics
Age^a	38.8	(10.5)	45.5	(10.3)	< 0.001	6.7
Sex f/m (%f)^b	710/482	(59.6)	188/162	(53.7)	0.060	n.a.
Level of education^c	3.96	(1.1)	3.72	(1.2)	< 0.001	0.2
CAG-repeat^a	42.5	(2.6)	43.8	(3.1)	< 0.001	1.3
Clinical characteristics
UHDRS-TMS^a	3.9	(6.4)	14.8	(11.7)	< 0.001	10.9
SDMT^a	50.5	(12.4)	37.7	(12.7)	< 0.001	12.8
SCNT^a	72.8	(15.2)	59.6	(15.2)	< 0.001	13.2
SWRT^a	93.5	(18.2)	79.4	(18.0)	< 0.001	14.2
SIT^a	43.8	(11.2)	34.7	(10.9)	< 0.001	9.1
TMT-A^a	27.8	(13.7)	38.7	(21.3)	< 0.001	10.9
TMT-B^a	59.1	(35.3)	95.9	(60.1)	< 0.001	36.8
Apathy^d	0	(0 –0)	0	(0 –2)	< 0.001	0
Anxiety^d	4	(2 –7)	5	(3 –8)	< 0.001	1
Depression^d	2	(0 –5)	4	(2 –7)	< 0.001	2

UHDRS-TMS, Unified Huntington Disease Rating Scale-Total Motor Score; SDMT, Symbol Digits Modalities Test; SCNT, Stroop Color Naming Test; SWRT, Stroop Word Reading Test; SIT, Stroop Interference Test; TMT-A, Trail Making Test-A; TMT-B, Trail Making Test-B; n.a., not applicable; Significant differences in bold. ^aComparison by means of an independent sample t-test, the mean and standard deviation are reported. ^bComparison by means of a chi-squared test, the number of female and male participants are reported. ^cComparison by means of a Mann-Whitney U test, the mean and standard deviation are reported. ^dComparison by means of a Mann-Whitney U test, the median and interquartile range are reported. ^eFor the level of education, apathy, anxiety and depression the median difference is reported. Mean differences are reported for all other variables except for sex.

When adjusting all demographic and clinical characteristic for each other in a multivariate cox regression performed on the premanifest HD, age, CAG-repeat length and apathy were significantly associated with changes in working capacity over time (Table 3). An increase in apathy score over a period of three years indicated a 14%higher risk of losing working capacity (HR = 1.14, 5%CI 1.04–1.25, p = 0.006). Multivariate cox regression performed on the manifest participants showed significant associations between age, CAG-repeat, SDMT, TMT-A, SWRT, UHDRS-TMS and the changes in working capacity over time (Table 3).

Table 3

Multivariate cox regressions associating demographical and clinical characteristics with changes in working capacity in premanifest and manifest HD participants

	Premanifest			Manifest
	HR^a	95%CI for HR	p	HR^a	95%CI for HR	p
Demographics
Age	1.06	(1.03 –1.09)	< 0.001	1.05	(1.03 –1.07)	< 0.001
Sex	0.89	(0.54 –1.46)	0.648	0.88	(0.68 –1.14)	0.324
Level of education	1.02	(0.83 –1.24)	0.885	0.97	(0.86 –1.08)	0.547
CAG-repeat	1.23	(1.11 –1.38)	< 0.001	1.13	(1.06 –1.20)	< 0.001
Clinical characteristics
UHDRS-TMS	1.12	(0.96 –1.31)	0.706	1.03	(1.01 –1.04)	< 0.001
SDMT	1.04	(0.98 –1.03)	0.966	0.97	(0.95 –0.98)	< 0.001
SCNT	1.00	(0.97 –1.03)	0.661	0.99	(0.98 –1.00)	0.367
SWRT	1.00	(0.98 –1.01)	0.456	1.01	(1.00 –1.02)	0.035
SIT	0.99	(0.96 –1.02)	0.484	0.99	(0.98 –1.01)	0.579
TMT-A	1.01	(0.98 –1.03)	0.102	0.99	(0.98 –1.01)	0.019
TMT-B	1.01	(1.00 –1.02)	0.158	1.00	(1.00 –1.00)	0.720
Apathy	1.14	(1.04 –1.25)	0.006	1.04	(0.99 –1.10)	0.155
Anxiety	1.06	(0.98 –1.14)	0.138	1.02	(0.98 –1.06)	0.450
Depression	1.00	(0.91 –1.10)	0.965	1.03	(0.98 –1.08)	0.216

DISCUSSION

The current longitudinal study is the first to determine predictors of working capacity in HD over time. We found that higher motor dysfunction, lower psychomotor speed, higher levels of apathy, higher age, and a higher CAG-repeat are associated with shorter time to (partial) loss of working capacity. This study showed that there are no clinically relevant differences between HD expanded gene carriers and healthy controls who were employed at baseline. Therefore, an HD expanded gene carrier status in itself does not imply an incapacity for employment. Nor does the manifestation of HD, as more than 50%of the participants in this study who had a normal working capacity at baseline but lost their job at follow-up had already received clinical diagnoses. However, we have shown that the chance of experiencing changes in employment within three years from baseline is almost eight times higher for HD expanded gene carriers compared to healthy controls.

Being employed attributes to feelings of independence, provides daily structure, and helps to maintain financial autonomy [10]. Thus, loss of employment has a profound impact on an HD expanded gene carriers and their family. In line with previous studies, we have shown that working capacity changes are not only subject to motor dysfunction. The changes also relate to psychiatric and cognitive symptoms which play an important role in early stages of the disease [9 , 12]. In addition, this emphasizes the symptom heterogeneity of disease onset in HD. The results of the current study are to a great extent comparable with studies of employment in Parkinson’s disease (PD). A recent review on early retirement of PD-patients showed that motor symptoms as well as non-motor symptoms have a detrimental effect on the ability to work. Motor symptoms like slowness, stiffness and tremor were good predictors of early retirement, as were non-motor symptoms like fatigue, anxiety, memory deficits, concentration problems and depression [25]. Previous cross-sectional studies have indicated depression to be related to unemployment in HD, which we did not find in our current study [11]. The difference in findings, might be explained by depressive symptoms arising as a consequence and not as a cause of unemployment. Nor did participants who had a steeper decline in employment status (e.g., complete loss of employment vs. a reduction in work hours/tasks) report higher levels of depression on a clinically relevant level. Apathy [12] however, was found to be of value in predicting change in employment status.

The most consistent determinants of change in working capacity were age and CAG-repeat length. The latter has been reported in a prior study as an important factor of workplace impairment [11]. In combination with age, however, it quite possibly reflects disease progression. Studies have shown that a higher CAG-repeat length will contribute to an earlier manifestation of disease specific characteristics [26]. Thus, as age and the disease progress, the probability of experiencing changes in employment status becomes higher. Furthermore, this effect was found to be the largest for premanifest HD.

When further distinguishing between premanifest and manifest HD expanded gene carriers, noticeable differences were found in clinical determinants of change in working capacity. In manifest HD, working capacity is strongly influenced by motor and cognitive impairment, reflecting the heterogeneity of the progressing disease. In contrast, premanifest HD expanded gene carriers are influenced mainly by symptoms of apathy, which, interestingly enough, has been coined as a possible marker for disease progression and is more prevalent in manifest HD [27]. As low levels of apathy measured by the PBA-s could indicate something more like fatigue or dysthymic mood, this might also reflect burn-out-like symptoms. However, more specific research into burn-out and HD is needed to investigate this possible relationship.

We have included a very specific selection of participants from a larger database which consists of 15,301 unique baseline inclusions. The substantial reduction of included participants in this study is explained by the relatively small number of HD expanded gene carriers who had normal working capacity at baseline and had a minimum of one follow-up visit in three years. Although this enables us to focus on HD expanded gene carriers who are at the beginning of changes in working capacity, it prevents us from addressing work related problems of HD expanded gene carriers who are already experiencing problems with working capacity. This, however, should be a topic in future studies.

Another weakness of the study pertains to the effect of the symptoms of HD on specific job requirements, which can be subjective and might also not be universal. For instance, one warehouse manager might be continually seated at a computer whereas another might be required to physically assist in a warehouse. For the first manager, intact cognitive function might be the most important occupational concern whereas the second manager might experience significant problems from motor dysfunction. These specific job requirements are not identified by the most commonly used scale, the UHDRS-TFC. To address these specific job requirements, the Huntington Disease Work Function scale (HDWF) has been constructed; however, it has yet to be implemented for research purposes [28], nor has research focused on the influence of work environments and work adjustments made by both employees and employers. As all these factors might have implications for the approach to work adjustments, future research should focus on understanding their influence on work functioning.

Our research supports that early changes in the clinical characteristics of the disease, even in the premanifest stage, can affect working capacity. Given the financial, psychological and personal consequences of becoming unemployed, we recommend clinicians to inform patients who are at-risk about the effects of early changes on employment due to HD. It is vital to understand that neither having an expanded gene nor a manifestation of the disease in itself is a reason to cease employment or make radical occupational changes. However, patients and families should recognize that early changes in all clinical aspects of the disease can affect the ability to perform at normal working capacity.

Footnotes

ACKNOWLEDGMENTS

The study was funded by the Leiden University Medical Center.

Enroll-HD is a clinical research platform and longitudinal observational study for Huntington’s disease families intended to accelerate progress towards therapeutics; it is sponsored by CHDI foundation, a nonprofit biomedical research organization exclusively dedicated to collaboratively developing therapeutics for HD. Enroll-HD would not be possible without the vital contribution of the research participants and their families.

We also like to acknowledge S. Feleus, MD and H.S. Bakels, MD for their feedback and contributions to this manuscript.

CONFLICT OF INTEREST

The authors declare no conflicts of interest.

ETHICAL COMPLIANCE STATEMENT

We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. All Enroll-HD sites were required to obtain and maintain local ethics committee approvals. Participants in the Enroll-HD study must have signed informed consent forms for their data to be included in the datasets.

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